Lecture 4: Pharmacology Cell Wall Inhibitors

Anti-infective

umbrella term including agents or substances with antibacterial, antiviral, and antifungal properties

Antibiotic

A chemical that kills bacteria or slows their growth without harming body cells.

Antifungal

an agent that destroys or inhibits the growth of fungi

Bacteriostatic

inhibits bacterial growth

Bactericidal

kills bacteria

can cause cell to lyse

General name vs Brand name

prescriptions need to be generic name

Ex. urinatilfloxacin/utinkle

Time-dependent kill

maximize time that the concentration is greater than MIC

3-5x greater than MIC

why drugs are dosed multiple times a day or on an infusion

Concentration-dependent kill

bigger peak above minimum inhibitory concentration (MIC)=bigger kill

peak= 10-20% MIC

Mechanism of Action (MOA)

How a drug produces its effects in the body

infections: how does a drug kill a bug

Minimum Inhibitory Concentration (Break Points)

lowest concentration of a drug that prevents visible growth of a microorganism

Post antibiotic effect

organisms do not grow for several hours even after discontinuation of medication

below MIC level but still effective

Cidal vs Static

relationship between one specific pathogen and an antibiotic

cidal= > 3 log kill in 24 hours

static= < 3 log kill in 24 hours

What is a LOG Kill (Reduction)?

1 Log= reducing the organism load by 90%

2 Log= 99%

3 Log= 99.9%

etc....

Gram Positive Organism

thick peptoglycan wall w lipid bilayer underneath

purple=positive

Gram Negative Organism

contains LPS and lipid layer and porins w a smaller peptoglycan cell wall underneath and finally a traditional lipid bilayer

pink/red=negative

Mycobacterium

more difficult to treat due to very waxy (non-penetrable) cell wall

cell wall contains LAMs, Acyl lipids, mycolates, arabino-galactin, then peptoglycan cell wall underneath and finally a traditional lipid bilayer

AFB stain to test for mycobacterium

Cell Wall Synthesis

1. Start material synthesis

2. Peptidoglycan synthesis

3. Peptidoglycan crosslinking

PBPs

- Penicillin Binding Proteins

- link peptidoglycan strands and catalyze controlled degradation for new growth

ex. beta lactams

D-ala-D-ala

small two-part molecule that bacteria use to build their outer protective cell wall

Beta-Lactams

Penicillins

Cephalosporins

Carbapenems

Monobactams

& all associated BLICs (ex. augmentin- add in enzyme inhibitor)

Classical/Natural Penicillins (PCNs)

old and cheap

Pen VK

Pen G

Benzathine

Pen VK

Classic/Natural PCN (beta-lactam)

Route: PO

Coverage: Gram +

Indications: strep throat & dental infections

Contraindications: tastes bad

Misc: requires frequent dosing

Pen G

Classic/Natural PCN (beta-lactam)

Route: IV

Coverage: Gram +

Indications: DOC for CNS manifestations of syphilis and major strep infections

Benzathine

Classic/Natural PCN (beta-lactam)

Route: IM

Coverage: Gram +

Indications: DOC for primary and secondary syphilis; can use depot for strep

depot: long-acting, slow-release injectable formulation; detectable levels for 2-4 weeks

Antistaphylcoccal PCNs

penicillinase resistant

Dicloxacillin

Nafcillin

Oxacillin

Methicillin

Dicloxacillin

Antistaphylcoccal PCN

Route: PO

Coverage: Gram + S. aureus

Indications: bactericidal against MSSA, "sensitive S. aureus" not commonly used

Nafcillin

Antistaphylcoccal PCN

Route: IV

Coverage: Gram + S. aureus

Indications: bactericidal against MSSA, "sensitive S. aureus" not commonly used

Contraindications: can burn veins in some pts

Misc: most hospitals have in stock

Oxacillin

Antistaphylcoccal PCN

Route: IV

Coverage: Gram + S. aureus

Indications: bactericidal against MSSA, "sensitive S. aureus" not commonly used

Contraindications: can burn veins in some pts

Misc: used to run sensitivity/resistance testing

Methicillin

Antistaphylcoccal PCN

Route: IV

Coverage: Gram + S. aureus

Indications: bactericidal against MSSA, "sensitive S. aureus" not commonly used

Contraindications: can burn veins in some pts

Misc: not used anymore

Aminopenicillins

CHEAP

Ampicillin

Amoxicillin

Ampicillin

Aminopenicillin

Route: PO & IV

Coverage: > Gram + & < Gram -

Indications: DOC for Listeria, most cidal drug for sensitive enterococcus Contraindications: GI Issues

Amoxicillin

Aminopenicillin

Route: PO

Coverage: > Gram + & < Gram -

Indications: Strep throat, otitis media, CA-P (if caused by S. pneumo); sensitive & intermediate Strep pneumo

Misc: commonly prescribed; achieves higher levels and fewer doses than ampicillin Contraindications: GI Issues

Anti-Gram Negative PCNs

Piperacillin

Zosyn (piperacillin + taxobactam)

Piperacillin

Anti-Gram Negative PCNs

Route: IV

Coverage: Gram - & Fair Gram + (not MRSA or resistant strep pneumo) & some anaerobe activity (inside body only)

Indications: Pseudomonas aeurginosa (PA), enterococcus, UTI, bone & joint infections, skin infections

Misc: need 16g/day for optimal coverage of PA

Zosyn (piperacillin + tazobactam)

Anti-Gram Negative PCNs & BLIC

Route: IV

Coverage: Gram - & Fair Gram + (not MRSA or resistant strep pneumo) & some anaerobe activity (inside body only)

Indications: Pseudomonas aeurginosa (PA), enterococcus, UTI, bone & joint infections, skin infections

Contraindications: does not get into the head well

Misc: Tazobactam = BLIC

Does not cover MRSA or atypicals

Beta-Lactam Antibiotic Generic Names: cephalosporins

Cefazolin

Cephalexin

Cefuroxime

Ceftriaxone

Cefotaxime

Cefepime

Cefteraline

First Gen Cephalosporins

First place = +

Cephalexin (Keflex)

Cefazolin (Ancef)

Cephalexin (Keflex)

1st gen cephalosporin

Route: PO

Coverage: Gram + (better coverage) Gram - (basic coverage)

Indications: Skin infections, MSSA, Staph, Strep throat, some E. coli

Misc: good alternative to antistaphylococcal PCN

Cefazolin (Ancef)

1st gen cephalosporin

Route: IV

Coverage:Gram + (better coverage) Gram - (basic coverage)

Indications: Skin infections, MSSA, Staph, Strep throat, some E. coli

Misc: Surgical prophylaxsis; good alternative to antistaphylococcal PCN

Second Gen Cepahlosporins

"2 Furry Foxes Drinking Tea"

Cefuroxime (Ceftin)

Cefuroxime (Zinacef)

Cefoxitin

Cefotetan

Cefuroxime (Ceftin)

Second Gen Cephalosporin

Route: PO

Coverage: gram - (better coverage) & gram + (some)

Indications: COPD, smokers w bronchitis from H. flu, M. cat, UTI

Contraindications: short half life

Cefuroxime (Zinacef)

Second Gen Cephalosporin

Route: IV

Coverage: gram - (better coverage) & gram + (some)

Indications: COPD, smokers w bronchitis from H. flu, M. cat, UTI

Contraindications: short half life

Misc: surgical prophylaxsis

Cefoxitin

Second Gen Cephalosporin

Route: IV

Coverage: basic anaerobe coverage; gram -

Indications: intra-abdominal pelvis infections, H. flu, M. cat

Contraindications: short half life

Misc: surgical prophylaxsis

Cefotetan

Second Gen Cephalosporin

Route: IV

Coverage: basic anaerobe coverage; gram -

Indications: intra-abdominal pelvis infections, H. flu, M. cat

Contraindications: short half life

Misc: can inhibit vit K production & prolong bleeding; used in gut surgeries & aspiration pneumonias; OBGYN prophylaxsis

Third Gen Cephalosporins

Third place = -

You can TRI TAXing me but you won't get a DIME

Ceftazadime (Fortaz)

Ceftriaxone (Rocephin)

Cefotaxime (Claforan)

Cefpodoxime (Vantin)

Cefdinir (Omnicef)

Ceftazadime (Fortaz)

Third Gen Cephalosporin

Route: IM or IV

Coverage: Gram -

Indications: Pseudomona aeruginosa

Contraindications: Potent inducer of beta-lactamase esp in enterobacter (dont use alone)

Misc: need a high dose for PA (2g IV q8)

Ceftriaxone (Rocephin)

Third Gen Cephalosporin

Route: IM or IV

Coverage: > Gram + & < Gram - (basic)

Indications: DOC for N. meningitides (dosed 2g q12), strep pneumo, gonorrhea, lyme disease

Contraindications: don't give within 24 hours of calcium products or TPN; avoid in neonates

Misc: Gets into CNS well; all other tx dosed 2g q24 IV

Cefotaxime (Claforan)

Third Gen Cephalosporin

Route: IM or IV

Coverage: Gram + & Gram - (basic)

Indications: Strep pneumo

Misc: Renal elimination; used in NICU

Cefpodoxime (Vantin)

Third Gen Cephalosporin

Route: PO

Coverage: more drug > Gram + & less drug < Gram - (basic)

Indications: Strep pneumo, H. flu, M. cat

Misc: expensive$$$; can inhibit vit K

Cefdinir (Omnicef)

Third Gen Cephalosporin

Route: PO

Coverage: more drug > Gram + & less drug < Gram - (basic)

Indications: Strep pneumo, H. flu, M. cat

Misc: $$$

Cefepime (Maxipime)

Fourth Gen Cephalosporin (Cef-4-pime)

Route: IV

Coverage: Gram - & Gram + (basic)

Indications: Psuedomonas aeruginosa, streptococci, Strep pneumo, MSSA

Contraindications: Gets into head well

Misc: neurotoxicity

Cefteraline (Teflaro)

Fifth Gen Cephalosporin (Cef-STAR-line)

Route: IV

Coverage: Gram - & Gram +

Indications: MRSA/MSSA, Strep pneumo, Kleb pneumo, E. coli, some enterococcus, CA-P

Misc: only B-lactam to cover MRSA

Ceftobiprole (Zevtera)

Cephalosporin FDA-approved in mid 2024

Route: IV

Indications: MRSA/MSSA coverage; some GNR

Beta-Lactam Antibiotic Generic Names: Carbapenems

BIG GUNS=BIG COVERAGE

Imipenem

Metropenem

Doripenem

Ertapenem & Tebipenem

Imipenem

Carbapenem

Route: IM or IV

Coverage: Gram + , Gram - , Anaerobes, Atypicals

Indications: MSSA, Streptococci, anaerobes, enteric gram - rod (GNRs), Pseudomonas, nasty GNRs

BIG GUNS = BIG COVERAGE = Extremely broad spectrum

Misc: may induce seizures; does NOT cover S. maltophilia

Meropenem

Carbapenem

Route: IM or IV

Coverage: Gram + , Gram - , Anaerobes, Atypicals

Indications: MSSA, Streptococci, anaerobes, enteric gram - rod (GNRs), Pseudomonas, nasty GNRs

BIG GUNS = BIG COVERAGE = Extremely broad spectrum

Misc: Expensive $$$

Doripenem

Carbapenem

Route: IM or IV

Coverage: Gram + , Gram - , Anaerobes, Atypicals

Indications: MSSA, Streptococci, anaerobes, enteric gram - rod (GNRs), Pseudomonas, nasty GNRs

BIG GUNS = BIG COVERAGE = Extremely broad spectrum

Ertapenem

Carbapenem

Route: IM or IV

Coverage: Gram + , Gram - , Anaerobes, Atypicals

Indications: MSSA, Streptococci, anaerobes, enteric gram - rod (GNRs), nasty GNRs

BIG GUNS = BIG COVERAGE = Extremely broad spectrum

Misc: ONLY carbapenem that does NOT cover pseudomonas

Tebipenem (Utebzi®)

New carbapenem (2026)

Route: PO

Indication: complicated UTI

Misc: coverage more like ertapenem; no significant coverage of Pseudomonas aeruginosa

Aztreonam (Azactam)

ONLY Monobactam

Route: IM or IV

Coverage: Gram -

Indications: Gram - infections including pseudomonas, particularly in pts with hx of beta-lactam allergy

Contraindications: resistance issues due to overuse; no cross reactivity with other beta lactam abx

Misc: expensive $$$ but can be use in pts w PCN or ceph allergy

BLICs

Augmentin (amoxicillin/clavulanic acid)

Zosyn (piperacillin/tazobactam)

Unasyn (ampicillin/sulbactam)

Avycaz (ceftazidime/avibactam)

Zerbaxa (ceftolozane/tazobactam)

Vabomere (meropenem/vaborbactam)

Recarbrio (imipenem/relebactam)

Emblaveo (aztreoname/avibactam)

Xacduro (sulbactam/durlobactam)

Augmentin (Amoxicillin/Clavulanic Acid)

BLIC

Route: PO

Coverage: Gram - (basic), basic anaerobes, sensitive enterococcus, gram +

Indications: DOC for OM, acute sinusitis (H. flu & M. cat), animal bites, human bites, aspiration pneumonia

Contraindications: GI upset/diarrhea

Misc: does NOT cover Strep pneumo or MRSA

Zosyn (piperacillin/Tazobactam)

BLIC

Route: IV

Coverage: Gram - , Fair Gram +, some anaerobe

Indications: pseudomonas aeruginosa, enterococcus, bone & joint infections, skin infections

Contraindications: does not go into head well

Misc: to treat PA you need higher dose

Unasyn (ampicillin/sulbactam)

BLIC

Route: IV

Coverage: Gram - (basic), Gram + (weak), basic anaerobe

Indication: covers all of Ampicillin organisms plus basic anaerobes

Misc: NO nasty GNR or PA coverage

Avycaz (ceftazidime/avibactam)

BLIC

Route: IM or IV

Coverage: Gram -

Indications: Carbapenem-resistant Enterobacterales (CRE)

Misc: restores activity lost to b-lactamase producers

Zerbaxa (ceftolozane/tazobactam)

BLIC

Route: IM or IV

Coverage: Gram - & anaerobes

Indications: Pseudomonas aeruginosa & B. frag (anaerobe)

Vabomere (meropenem/vaborbactam)

BLIC

Route: IM or IV

Indications: Carbapenem-resistant Enterobacterales (CRE), Klebsiella pneumoniae Carbapenemase (KPC)

Recarbrio (imipenem/relebactam)

BLIC

Route: IM or IV

Indications: Carbapenem-resistant Enterobacterales (CRE), Klebsiella pneumoniae Carbapenemase (KPC), some resistant PA

Emblaveo (aztreoname/avibactam)

new BLIC 2025 approval

Route: IV

Indications: GNR (CRE & MVL producers); no anaerobe coverage

Xacduro (sulbactam/durlobactam)

BLIC

Route: IV

Indications: CRAB (carbabenemase-resistant acinetobacter baumannii)- difficult to treat Gram -

Glycopeptides

Vancomycin

Dalbavancin

Oritavancin

Vancomycin

Glycopeptide

Route: PO or IV

Coverage: Gram +

Indications: DOC for C. diff colitis (PO); IV: MRSA, Strep pneumo, meningitis

Contraindications: CNS penetration low, risk of VRE with overuse, red man syndrome infused too quickly

Misc: adult dose is 30mg/kg/day q12, double for meningitis

Oritavancin (Orbactiv)

Glycopeptide

Route: IM or IV

Coverage: Gram +

Indications: MRSA

Contraindications: no heparin within 48 hrs of dose

Misc: single 1200 mg dose lasts 7-10 days; long half life

Dalbavancin (Durata)

Glycopeptide

Route: IM or IV

Coverage: Gram +

Indications: MRSA

Misc: 1000mg week one, 500mg week two; long half life

Other Cell Wall Players

Daptomycin, Fosfomycin, Bacitracin (topical and OTC)

Daptomycin (Cubicin)

Route: IV

Coverage: Gram +

Indications: MRSA & VRE

Contraindications: will destroy lung surfactant in pnemonia pts

Misc: expensive $$$

Fosfomycin

Route: PO (powder)

Coverage: Gram - , some Gram +

Indications: uncomplicated cystitis in women w adequate renal function, UTI

Misc: not for systemic use, low bioavailability, safe for pregnancy

Bacitracin

Route: Topical (ointment/cream) OTC

Coverage: Gram +

Indications: Staphylococcus aureus (including some MRSA strains topically), Streptococcus, some gram-positive anaerobes

Contraindications: hypersensitivity & anaphylaxsis risk

Misc: Ex. neosporin

Beta Lactam Ring Structure

Ring has to be intact for antibiotic to work

all beta-lactams have the ring structure- each beta-lactam drug has minor differences but the ring is always present

Aztreonam is the one beta-lactam that you can give to a pt with a penicillin allergy

Beta-Lactams MOA

impacts penicillin-binding proteins (PBP) screwing up cell wall

interferes with transpeptidation reaction which impacts cross-links and ultimately, rigidity/function of wall

there are several sub-groups of PBPs... some drugs more selective for certain PBP sub-groups

PK/PD: 'cidal and time dependent killing- short T1/2 (multiple doses/day or infusion)

Beta-Lactam Resistance Mechanisms

Organism dependent- one size does NOT fit all

Alterations in PBPs Ex: S. pneumoniae- push for low-intermediate level resistance

Beta-lactamases Ex: H influenzae- use BLIC agent to "bait" beta-lactamases.... or use agent MORE STABLE to beta-lactamase

Carbapenamases

Enzymes that confer resistance to carbapenems

Ex. nasty gram negs; KPC, NDM, OXA-48

SPACE bugs

nasty gram negatives

Serratia

Pseudomonas

Acinetobacter

Citrobacter

Enterobacter

Allergies to ABX

Skin eruptions most common- often IgE mediated- this decreases 10%/year w age

PCN vs Cephalosporin: 7-10% cross reactivity, lower w later generations; almost NONE with monobactam