Lecture 128: Beta Lactams, Cell Wall inhibitors and Cell Membrane inhibitors

How can microbiota cause infection?

when there is a break in barrier

Skin microbial pathogens

Staph aureus
Staph epidermidis
Streptococcus

Nasopharynx pathogens

Neisseria Meningitidis (gram -)
alpha hemolytic (viridens)
S aureus
non-hemolytic streptococci
Haemophilus
S pneumoniae

Gi microbes pathogens

Anaerobes:
- Bacteriodes fragilis (diff to treat)
- Clostridium
Facultative anaerobes (rods and bacilli):
- Gram + : enterobacterales, E coli, Klebseilla, Proteus mirabilus, Salmonella enterica, Shigella
Candida (fungus)
Gram -: Enterococcus faecalis, E faecium

Secondary infections

can come from antibiotic therapy
- the antibiotic will kill the bacteria and the ones that aren't killed will survive and increase in numbers

Colon: C difficile (spore forming gram +: diarrhea, pseudomembranous colitis, life threatening megacolon)

Vagina: Candida (yeast) can cause oral thrush

Structure of Peptidoglycan cell wall

amino sugars: NAG and NAM
- NAM has peptides attached
oligopeptides: crosslink through transpeptidases

Gram + vs gram -

Gram +: thick peptidoglycan layer, purple

Gram -: thin cell wall, outer membrane
periplasmic space (has enzymes)
- red stain

Beta Lactam antibiotics

Penicillins: narrow, extended (gram -) , anti-pseudomonas

Cephalosporins: narrow, extended spectrum, and ANTI-MRSA

Cabarpenems: broad spectrum

Monobactam: gram - aerobes

Cell wall antibiotics: vancomycin

Cell membrane antibiotics: daptomycin

Beta Lactams:

analogs of D-Ala-D-Ala

Beta Lactam antibiotics structure

- active if they have a Beta lactam ring
- bacterial beta lactamases cleave the b lactam ring (inactivate)
- different names based on side chains (stability and spectrum of activity)

Beta lactam class Absorption property

Oral, IM, IV
- IT contraindicated because it can cause arachnoiditis and encephalopathy

Distribution of Beta lactam classes

- widely distributed in body fluids
- poor penetration in CSF but can penetrate if meninges are inflamed
poor penetration in vitreous fluid and prostrate

Cephalosporins that can penetrate CNS

Ceftriaxone, cefotaxime, cefuroxime, cefepime

Elimination of beta lactam and half life

Elimination through renal (glomerular filtration/secretion)
Penicillinase resistant: hepatic metabolism

half life is short about 1 hour so frequently administered

What B lactam antibiotic has long half life?

ceftriaxone

PK-PD profile for Beta lactams

T > MIC
- the amount of time during the dosing interval that the
serum drug concentration stays above the MIC.
- minimum persistent effects
- bactericidal
time dependent

Target of Beta Lactams

- disrupt last step: cell wall crosslinking

B lactam binds transpeptidase (PBP) - block peptide cross linking - block cell wall synthesis - trigger bacterial autolysins (holes) - osmotic rupture and non lytic mechanisms

Acquired resistance to B lactams

Enzymatic degradation of drugs
- lactamases
- Staphylococcus (MSSA), GNBs

Modification of PBP drug target
- Staphylococcus (MRSA), S penumoniae, Enterococcus

Reduced drug concentration at site of target
- changes in porins in gram - that prevents drug from penetrating outer membrane
- efflux

Intrinsic resistance of B lactam

Obligate intracellular bacteria: beta lactams don't penetrate into host cells
- Atypicals: legionella, ricketssia, chlamydiae

lack cell wall: mycobacteria

Ways of Resistance to Beta lactam drugs

6 Ps
- penicilinases
- PBPs
- porins
- pumps
- penetration
- Peptidoglycan

Biofilm effect on antibiotics

- coating
- decreased rates of growth
- not growing as fast

What should you not use antibiotics for?

viral infections

What is antibiotic selection based on?

- site of infection
- spectrum of activity
- microbial resistance
- patient factors
- drug toxicity
- cost

Drug selection:

- drug with activity against infectious pathogen
- distributes to site of action
- therapeutic concentration
- proper route of administration
- not contraindicated

Adverse effects of penicillin

- on own, doesn't cause problems but forming hapten (covalent binding to RBC) can create a complex and stimulate immune attack = hemolytic anemia

Cross reactivity with other B lactams

will happen if side chains are similar
do skin testing to test allergy to medications
- most common causes of drug induced anaphylaxis

Anaphylaxis

rapid progressing, life threatening
hypotension, bronchoconstriction, death

treat: Airway, respiratory, cardiovascular support
− Epinephrine, antihistamines, glucocorticoids

Angioedema (vasculitis of deeper vessels):
• Serum sickness: delayed type III reaction (fever, rash, arthralgia, other features)
• Immune hemolysis ⇒ hemolytic anemia
• Rash; Stevens-Johnson syndrome / toxic epidermal necrolysis
• Fever; interstitial nephritis

Non-immunological side effects of B lactams

GI: mild to severe diarrhea; nausea; vomiting
Clostridioides difficile secondary infection: may cause significant morbidity or mortality (active drug excreted in feces increases risk)
Candidiasis (yeast) secondary infection: oral thrush, vaginal yeast infection
I.M. injection → pain; sterile inflammatory reaction may occur at injection site
I.V. injection → phlebitis or thrombophlebitis can occur

Special populations effect on B lactams

Pregnancy: generally compatible, no evidence of harm
Lactation: excreted in breast milk, can cause modifications to flora
Pediatrics: safe in neonates
Neonates: immature renal function - high half life

Probenecid interaction

inhibition of renal OAT (transporters) which lead to increased B lactam level

Oral contraceptives interaction with B lactam

estrogen/progesterin
- decrease estrogen recycling
- decreases efficacy because involved in enterohepatic circulation - glucuronide - cleaves and estrogen reabsorbed
- if anti-microbials kill bacteria, can't cleave glucuronide or reabsorb estrogen
pregnancy risk

Tetracycline effect with B lactams

bacteriostatic which can reduce B lactam efficiency leading to decreased Penicillin efficacy

Ambler Classification of Beta lactamases

Class A, C, D: Serine B lactamases
Class B: Metallo B lactamases

Class A Beta lactamases

ESBLs (extended spectrum B lactamases)
- TEM, SHV, CTX-M: resistance to Beta lactams

KPC: Carbapenemase

Usually this class blocked by inhibitors

Class C beta lactamases

Amp C: resistance to broad and extended spectrum beta lactam antibiotics
Multi drug resistant

Class B beta lactamases

not inhibited by any inhibitors
other carbapenemases

Mechanisms of Betal lactamase inhibitors

have weak antibacterial activity on own
- antibacterial spectrum determined by antibiotic

Adverse effects: hypersensitivity and secondary C diff reaction

Suicide irreversible inhibitors

Clavulanic acid, sulbactam, tazobactam
- inhibit class A lactamases
- have beta lactam structure

Potent reversible inhibitors

Avibactam, Vaborbactam, Relebactam, Durlobactam
- Inhibit Ambler class A, and C β-lactamases
- lack B lactam structure

Penicillins class

Narrow:
- Natural penicillins (penicillin G)
- Penicillinase-resistant penicillins

Extended spectrum:
- Aminopenicillins
- Antipseudomonal penicillins

Natural penicilins

highly active
- gram positive, aerobic, anaerobic
N meningitidis, spirochetes

Types:
Pen G (benzyl) and Pen V*( phenoxymethyl)

Penicilin's narrow spectrum of activity

- Gram +
- Gram - N meningitidis
- Spirochetes: Treponema Palidum (syphilis)
not effective against atypicals

What bacteria was penicilin effective before but now resistant?

Staph aureus and Staph epidermidis and Enterococcus faecum

Penicilin G and V mechanism

Pen G, aqueous: IV and IM: rapidly reached therapeutic conc

Pen V: only oral: more acid stable than Pen G, lower plasma concentrations - mild infections

Repository Pen G: IM only
- benzathine
- procaine
- combo of both

Why is IV administration of repository contraindicated?

cardiopulmonary arrest and death

Resistance Mechanisms of Natural Penicilins

Beta lactamases:
- S aureus and gram - bacilli

PBP alterations with low affinity for B lactams: S pneumoniae, MRSA, E faecum

Intrinsic resistance: gram - bacilli
- can't penetrate porins

Adverse Effects of Natural Penciliin

Seizures: High Dose Penicilin
Electrolyte imbalances: drugs formulated Na, K salts
- Pen G has short t 1/2 and T > MIC with minimal effects
- IV 6 times daily or continuous

Jarisch Herxheimer Reaction

- Syphilisl acute, self limited febrile reaction to penicilin
resolves in 12-24 hours without intervention

Proposed mechanism:
- immune reaction in response to lipoproteins released from spirochetes

Management: NSAIDS

Penicillinase-Resistant Penicillins

Isoxazolyl penicillins:
Nafcillin (IM, IV)
Oxacillin (IM, IV)
Dicloxacillin (oral)
Cloxacillin (oral)

Spectrum of Activity of Penicillinase-Resistant Penicillins

Gram + cocci
- S penumoniae
- Group A strep
- MSSA: S aureus
- MSSE: S epidermidis

PK, Resistance, Therapeutic use, Adverse effects of PRP

PK: hepatic elimination (non renal)
- dose adjustment not necessary for renal impairment

Resistance: PBP2a (MecA): very low affinity for all beta lactam antibiotics
Therapeutic use:
- MSSA/MSSE infections only

Adverse effects:
- hepatitis: direct toxicity and hypersensitivity
- Acute interstitial nephritis

Aminopenicillins

higher affinity for PBPs and greater penetration through gram - outer membrane

Ampicilins (IM,IV oral, 50% availability) and Amoxicilin (Oral, 100% bioavailability, increased plasma levels)

Combination with B lactamase inhibitors expand activity by increasing stability against B lactamases
- Ampicilin sulbactam
- amoxicilin - clavulanate

Aminopenicilin's spectrum activity

Gram positive, gram - aerobes
- spirochetes: Borrelia burgdorferi
obligate G+ anaerobic: Clostridia SPP

Spectrum of Aminopenicilins

The aminopenicillins (extended-spectrum penicillins) have the gram-positive activity of penicillin G.
- A structural modification increases their spectrum to include gram- negative respiratory pathogens and some Enterobacterales

- Ampicillin is the drug of choice for Listeria
monocytogenes infections and susceptible enterococci

Resistance of amino penicilins

Modified PBPs:
MRSA, S. pneumoniae, Enterococcus
Class A ESBLs: Resistance can be overcome with the addition of beta-lactamase inhibitor.

- Bacteroides fragilis: (obligate anaerobic GNB*)
- Resistance can be overcome with the addition of beta-lactamase inhibitor.
Intrinsic resistance: Pseudomonas aeruginosa

Adverse effects of Aminopenicilins

Non-allergic rash:
Maculopapular rash on trunk and may spread
to face; usually appears 5-7 days from the
start of therapy

Incidence is higher in patients with:
- Viral infection such as Roseola or
mononucleosis
- Allopurinol + ampicillin or amoxicillin
Differentiate allergic reaction:
- Onset of pruritic urticarial rash within hours of
first dose, cough, fever, and wheezing /
difficulty breathing.

Aminopenicilin class properties

Not metabolized
⋅ High concentrations excreted in urine.
⋅ Unabsorbed oral ampicillin excreted in feces
→ disruption of microbiota
⋅ Short half-life: Ampicillin IV may be administered by continuous infusion.

Antipseudomonal peniclins

Piperacillin-tazobactam (parenteral only)

Properties:
- Not metabolized
⋅ High concentrations excreted in urine.
⋅ Short half-life: IV may be administered by continuous infusion

Antipseudomonal peniclins spectrum of activity

not effective against T palidum, B burgdorferi (spirochetes), Clostridia (gram + anaerobe), N gonnorhea (Gram -), atypicals

Piperacillin-tazobactam

The broadest antibacterial spectrum of the penicillins class

- The same activity as the aminopenicillins plus
Pseudomonas aeruginosa
- Polar side chains allow the drug to pass through the porins
of P. aeruginosa and many GNBs (gram-negative bacilli).

Therapeutic uses: Bacteremia, pneumonias, burns, appendicitis, gynecologic, urinary tract infections

Adverse effects of Piperacillin-tazobactam

Congestive heart failure exacerbation: Na+ salts, frequent administration
Abnormal platelet aggregation, thrombocytopenia → bleeding disorders
Leukopenia/neutropenia (long-term use)
Seizure disorders (high doses; renal impairment)

Which antibiotic is the standard therapy for primary, secondary, or early latent syphilis?

A. Penicillin G

B. Penicillin V

C. Amoxicillin

D. Vancomycin

A

A single dose of benzathine penicillin G is the standard therapy for primary, secondary, or early latent syphilis caused by the spirochete Treponema pallidum, providing low but persistent serum levels of penicillin.

What is the most common mechanism of beta-lactam antibiotic resistance to gram-negative bacteria?

A. Alteration of penicillin-binding proteins

B. Decreasing penicillin concentration with efflux pumps

C. Production of beta-lactamases by bacteria

D. Modification of bacterial cell wall structure

C

The most common mechanism of beta-lactam antibiotic resistance to gram-negative bacteria is the production of beta-lactamases. These enzymes degrade the beta-lactam ring, rendering these antibiotics ineffective.

For which of the following bacterial infections is empiric treatment with nafcillin, oxacillin, or dicloxacillin most appropriate?

A. Bacterial cervicitis

B. Bacterial meningitis

C. Pyelonephritis

D. Skin and soft tissue infections

D

When given orally, anti-staphylococcal antibiotics are suitable for treatment of mild to moderate localized Staphylococcus aureus infections. Nafcillin, for example, is commonly used empirically to treat skin and soft tissue infections (e.g., folliculitis, abscesses), for which Staphylococcus aureus is the usual cause.

Why are anti-staphylococcal penicillins not effective against MRSA?

A. MRSA does not produce penicillin binding proteins

B. MRSA produces penicillin binding proteins with low affinity for beta-lactam antibiotics

C. MRSA enzymatically converts the penicillin to a non-effective form

D. MRSA neutralizes the effect of the penicillin via its efflux pump

B

Methicillin-resistant Staphylococcus aureus (MRSA) produces altered penicillin-binding proteins that have a low affinity for binding beta-lactam antibiotics. This renders anti-staphylococcal penicillins ineffective.

Which of the following best describes the mechanism of action shared by tazobactam and sulbactam?

A. Binding of penicillin binding protein

B. Binding to the bacterial cell wall

C. Inhibition of bacterial ribosomes

D. Inhibition of β-lactamase

D

Tazobactam and sulbactam inhibit bacterial β-lactamases. These drugs protect penicillin antibiotics from destruction by β-lactamases, enabling penicillin-based therapy for bacteria such as methicillin-sensitive Staphylococcus aureus.

Which of the following statements best describes the pharmacokinetic properties of the amino-penicillins amoxicillin and ampicillin?

A. Amoxicillin and ampicillin have equivalent oral bioavailability

B. Amoxicillin has higher oral bioavailability than ampicillin

C. Ampicillin has higher oral bioavailability than amoxicillin

D. Neither amoxicillin nor ampicillin can be given orally

B

The amino-penicillins, amoxicillin and ampicillin, have similar spectrums of activity, but amoxicillin has better oral bioavailability.
Mnemonic:

• aMOxicillin = by MOuth

• AMPicillin = AMPules (IV use)

Amoxicillin is typically used orally for pediatric illnesses like otitis media, sinusitis, or pharyngitis. Ampicillin is usually given intravenously for more serious infections needing anaerobic coverage (e.g., aspiration pneumonia).

Which of the following potential adverse effects is not associated with ampicillin or amoxicillin use?

A. Antibiotic-induced rash in the setting of viral illness

B. Drug-induced liver injury

C. Drug-induced rhabdomyolysis

D. Stevens-Johnson syndrome

C

Rhabdomyolysis involves breakdown of skeletal muscle and is commonly seen with statins, crush injuries, or intense physical activity (e.g., marathon running).
Ampicillin and amoxicillin are not associated with drug-induced rhabdomyolysis.
They are associated with:

• Rash (especially in viral illness like EBV)

• Liver injury

• Rarely, Stevens-Johnson syndrome

A 34-year-old man with a history of IV drug use presents with fever and a new systolic murmur. Blood cultures grow methicillin-sensitive Staphylococcus aureus (MSSA). Which of the following is the most appropriate antimicrobial therapy?

A. Penicillin V
B. Ceftriaxone
C. Nafcillin
D. Vancomycin
E. Amoxicillin-clavulanate

C

Correct Answer: C (Nafcillin) ✅

Explanations:

• A. Penicillin V – Narrow spectrum, oral only, ineffective against penicillinase-producing MSSA.

• B. Ceftriaxone – Broad-spectrum cephalosporin, but not first-line for MSSA.

• ✅ C. Nafcillin – A penicillinase-resistant penicillin; drug of choice for MSSA.

• ❌ D. Vancomycin – Used only if MRSA is suspected or in penicillin-allergic patients.

• E. Amoxicillin-clavulanate – Has activity against MSSA, but inferior to nafcillin for serious infections.

A 70-year-old woman with pneumonia is started on piperacillin-tazobactam. After several days of therapy, she develops leukopenia and abnormal platelet aggregation. These adverse effects are most likely due to:

A. Tazobactam-induced bone marrow suppression
B. Piperacillin accumulation due to hepatic dysfunction
C. High sodium load from parenteral piperacillin
D. Jarisch-Herxheimer reaction
E. Direct endothelial toxicity from tazobactam

C

Explanations:

• A. Tazobactam-induced bone marrow suppression – Incorrect; not a documented mechanism.

• B. Piperacillin accumulation due to hepatic dysfunction – Piperacillin is excreted renally.

• ✅ C. High sodium load from parenteral piperacillin – Causes CHF exacerbation and affects platelets.

• D. Jarisch-Herxheimer reaction – Seen in spirochete infections, not in this context.

• E. Direct endothelial toxicity – Not the mechanism of adverse hematologic effects here.