2.CW inhibit

What class of antibiotic is vancomycin?

Vancomycin is a:

• Glycopeptide antibiotic

• Cell wall inhibitor

Mainly active against:
→ Gram-positive bacteria

Mnemonic:
“VAN protects against Gram POSITIVE vans.”

What is the mechanism of action of vancomycin?

Vancomycin:

• Binds to D-Ala-D-Ala

• Blocks peptidoglycan elongation(stop polymerisation)

• Prevents bacterial cell wall synthesis

Result:
→ Weak cell wall
→ Bacterial death

Mnemonic:
“VAN parks on D-Ala-D-Ala.”

What organisms does vancomycin cover?

Strong activity against:

• MRSA

• MRSE

• Enterococci

• Other Gram-positive bacteria

NO significant activity against:

• Gram-negative bacteria

What does MRSA stand for?

Methicillin-Resistant Staphylococcus aureus

Vancomycin is a major treatment for MRSA.

What are the major clinical uses of vancomycin?

First-line treatment for:

• Complicated skin infections

• Bloodstream infections

• Endocarditis

• Bone & joint infections

• MRSA meningitis

When is oral vancomycin used?

Used for:

• Severe Clostridium difficile colitis

• Relapse cases

• Infection unresponsive to metronidazole

Important:

• Oral vancomycin stays in GI tract

• Poor systemic absorption

Mnemonic:
“PO VAN stays in the bowel.”

How is vancomycin administered?

IV Vancomycin:

• Serious systemic infections

• Slow infusion over 1–2 hours

Oral Vancomycin:

• C. difficile colitis only

Why must vancomycin be infused slowly?

Rapid infusion can cause:
→ Red Man Syndrome

Symptoms:

• Flushing

• Red rash

• Hypotension

• Itching

Cause:

• Histamine release

Prevention:

• Infuse slowly (1–2 h)

Mnemonic:
“Fast VAN = RED MAN”

What are the important adverse effects of vancomycin?

Major adverse effects:

• Red man syndrome

• Nephrotoxicity

• Ototoxicity

• Thrombophlebitis

Risk increases when combined with:

• Aminoglycosides

How is vancomycin eliminated?

Excreted unchanged by:

• Kidneys (glomerular filtration)

Clinical implication:
→ Dose adjustment needed in renal impairment

What is the resistance mechanism against vancomycin?

Bacteria change:

• D-Ala-D-Ala → D-Ala-D-Lac

This decreases vancomycin binding.

Example:

• VRE (Vancomycin-resistant Enterococci)

What combination therapy involving vancomycin is important?

Vancomycin + gentamicin:

• Alternative treatment for enterococcal endocarditis in severe penicillin allergy

Vancomycin + ceftriaxone/cefotaxime:

• Resistant pneumococcal meningitis

Why is vancomycin use restricted(limited)?

To reduce emergence of:

• VRE (Vancomycin-resistant Enterococci)

Used mainly for:

• Serious resistant Gram-positive infections

High-yield vancomycin exam pearl?

Vancomycin:

• Covers Gram-positive bacteria including MRSA

• Binds D-Ala-D-Ala

• Causes Red Man Syndrome if infused rapidly

• Oral form treats C. difficile

• Nephrotoxicity + ototoxicity are key toxicities

VAN parks on D-Ala-D-Ala, kills MRSA, turns patients RED if infused too FAST.”

What class of antibiotic is daptomycin?

Daptomycin is a:

• Lipopeptide antibiotic

• Cell membrane disruptor

Important:
→ NOT a cell wall inhibitor

What is the mechanism of action of daptomycin?

Daptomycin:

• Inserts into bacterial cell membrane

• Uses calcium-dependent binding

• Causes membrane depolarization

• Leakage of potassium ions occurs

Result:
→ Inhibits DNA, RNA & protein synthesis
→ Rapid bacterial death

Mnemonic:
“DAP = DePolarizes”

Is daptomycin bactericidal or bacteriostatic?

Daptomycin is:

• Rapidly bactericidal

• Concentration-dependent killer

What organisms does daptomycin cover?

Strong activity against resistant Gram-positive bacteria:

• MRSA

• VRE (Vancomycin-resistant Enterococci)

What are the major clinical uses of daptomycin?

Used for:

• Complicated skin infections

• MRSA bacteremia

• Right-sided infective endocarditis(a rare but life-threatening inflammation of the heart’s inner lining and valves, usually caused by bacterial or fungal infections)

Why should daptomycin NEVER be used for pneumonia?

Because:

• Pulmonary surfactant inactivates daptomycin

Result:
→ Ineffective in lungs

(Note: Linezolid has good lung penetration)

Mnemonic:
“DAP gets trapped by lung surfactant.”

What important adverse effects are associated with daptomycin?

Major toxicities:

• Myalgia(muscle pain)

• Muscle weakness

• Rhabdomyolysis

• Elevated creatine kinase (CK)

What monitoring is important during daptomycin therapy?

Monitor:

• Creatine kinase (CK) levels

Especially in:

• Patients on statins

• Muscle symptoms

What makes daptomycin unique compared with β-lactams and vancomycin?

Daptomycin:

• Targets cell membrane

• NOT cell wall

Mechanism:
→ Membrane depolarization

While β-lactams/vancomycin:
→ Inhibit cell wall synthesis

What is the high-yield exam point about daptomycin?

What is the high-yield exam point about daptomycin?

Back:
Key exam pearl:

• Covers MRSA & VRE

• Causes muscle toxicity

• Check CK

• NEVER use for pneumonia

Mnemonic:
“DAP DePolarizes muscles & can’t enter lungs.”

One-line summary of daptomycin?

Daptomycin is a lipopeptide antibiotic that kills resistant Gram-positive bacteria by depolarizing the bacterial membrane, but it cannot treat pneumonia because lung surfactant inactivates it.

What are the main polymyxin antibiotics?

Main polymyxins:

• Polymyxin B

• Colistin (Polymyxin E)

What class of antibiotics are polymyxins?

Polymyxins are:

• Polypeptide antibiotics

• Cell membrane disruptors

Important:
→ NOT cell wall inhibitors

What is the mechanism of action of polymyxins?

Polymyxins:

• Bind to phospholipids of Gram-negative bacteria

• Disrupt bacterial cell membrane integrity

Result:
→ Leakage of cell contents
→ Cell death

Mnemonic:
“POLYmyxin punches HOLES in membrane.”

Are polymyxins bactericidal or bacteriostatic?

Polymyxins are:

• Concentration-dependent

• Bactericidal

What bacteria are covered by polymyxins?

Strong activity against Gram-negative bacteria:

• Pseudomonas aeruginosa

• E. coli

• Klebsiella pneumoniae

• Acinetobacter species

• Enterobacter species

Do polymyxins work against Gram-positive bacteria?

No

Polymyxins mainly target:

• Gram-negative bacteria

Because they bind:
→ Lipopolysaccharide (LPS)

What are the major adverse effects of polymyxins?

Major toxicities:

• Nephrotoxicity

• Neurotoxicity

Examples of neurotoxicity:

• Slurred speech

• Muscle weakness

• Paresthesia

Mnemonic:
“POLY = kidney + nerve toxicity.”

Why is therapeutic drug monitoring (TDM) important for polymyxins?

Because polymyxins have:

• Narrow therapeutic index

• Significant nephrotoxicity/neurotoxicity risk

TDM helps:
→ Reduce toxicity

When are polymyxins usually used clinically?

Used mainly for:

• Severe multidrug-resistant Gram-negative infections

Especially when other antibiotics fail.

What is the membrane effect of polymyxins similar to?

Polymyxins act like:

• Detergents

They disrupt membrane integrity causing leakage.

What is the high-yield exam pearl for polymyxins?

Polymyxins:

• Target Gram-negative bacteria

• Bind LPS

• Destroy cell membrane

• Cause nephrotoxicity & neurotoxicity

Mnemonic:
“POLY punches holes → kidneys & nerves suffer.”

What class of antibiotic is fosfomycin?

Fosfomycin is:

• A bactericidal antibiotic

• A cell wall synthesis inhibito

What is the mechanism of action of fosfomycin?

Fosfomycin:

• Inhibits UDP-N-ag transferase (MurA)

This blocks:
→ The FIRST step of peptidoglycan synthesis

Result:
→ Inhibition of bacterial cell wall formation

Mnemonic:
“FOSFO = FIRST step OFF”

Is fosfomycin bactericidal or bacteriostatic?

Fosfomycin is:

• Bactericidal

Kills bacteria by blocking cell wall synthesis early.

What infections is fosfomycin mainly used to treat?

Mainly used for:

• Urinary tract infections (UTIs)

Especially caused by:

• E. coli

• Enterococcus faecalis

Why is fosfomycin effective for UTIs?

Because fosfomycin:

• Is rapidly absorbed orally

• Concentrates well in urine

• Maintains high urinary levels for several days

What are the pharmacokinetic properties of fosfomycin?

Fosfomycin:

• Rapid oral absorption

• Well distributed to:

  • Kidneys

  • Bladder

  • Prostate

• Excreted active in urine & feces

Often given as:
→ One-time dose for uncomplicated UTI

Does fosfomycin have cross-reactivity with β-lactams?

Unlikely

Because fosfomycin has:

• Unique chemical structure

Useful in some β-lactam allergic patients.

What are the adverse effects of fosfomycin?

Common side effects:

• Diarrhoea

• Nausea

• Headache

• Vaginitis

What is the high-yield exam pearl for fosfomycin?

Fosfomycin:

• Blocks the FIRST step of cell wall synthesis

• Used mainly for UTIs

• Given as single oral dose

• Concentrates in urine

Mnemonic:
“FOSFO stops the FIRST wall brick.”

What type of antibiotic is cycloserine?

Cycloserine is:

• A cell wall synthesis inhibitor

• An anti-tuberculosis (anti-TB) drug

Mainly used for:

• Drug-resistant tuberculosis

What is the mechanism of action of cycloserine?

Cycloserine:

• Inhibits alanine racemase

• Inhibits D-Ala-D-Ala formation

Result:
→ Prevents peptidoglycan synthesis
→ Weak bacterial cell wall

Mnemonic:
“CYCLO stops the D-Ala cycle.”

What bacteria is cycloserine mainly used against?

Used mainly for:

• Multidrug-resistant (MDR) tuberculosis

• Extensively drug-resistant (XDR) tuberculosis

Especially when:
→ First-line TB drugs fail

What are the pharmacokinetic properties of cycloserine?

Cycloserine:

• Water soluble

• Unstable at acidic pH

• Widely distributed into tissues

• Mainly excreted unchanged in urine

What is the most important toxicity of cycloserine?

Major toxicity:
→ CNS toxicity

Examples:

• Headache

• Tremors

• Acute psychosis

• Convulsions (seizures)

Mnemonic:
“CYCLO = CNS goes in circles.”

Why should cycloserine be used cautiously in epilepsy patients?

Because cycloserine can:

• Cause seizures

• Produce serious CNS toxicity

High risk in:

• Epileptic patients

• Psychiatric illness

What part of the cell wall pathway does cycloserine affect?

What part of the cell wall pathway does cycloserine affect?

Is cycloserine bactericidal or bacteriostatic?

Cycloserine is generally:

• Bacteriostatic against TB

But may be bactericidal at high concentrations.

What is the high-yield exam pearl for cycloserine?

Cycloserine:

• Treats MDR/XDR TB

• Blocks D-Ala formation

• Causes major CNS toxicity

Mnemonic:
“CYCLO affects the brain while stopping D-Ala chain.”

What type of antibiotic is bacitracin?

Bacitracin is:

• A polypeptide antibiotic

• A cell wall synthesis inhibitor

What is the mechanism of action of bacitracin?

Interferes with the dephosphorylation of C55- isoprenyl pyrophosphate

Result:
→ Inhibits bacterial cell wall synthesis

What bacteria does bacitracin mainly cover?

Mainly active against:

• Gram-positive bacteria

What is unique about bacitracin resistance?

Bacitracin has:

• No cross-resistance with other antimicrobial drugs

Why is bacitracin NOT used systemically?

Because bacitracin is:
→ Highly nephrotoxic

Can cause severe kidney damage if given systemically.

Mnemonic:
“BACI breaks kidneys.”

How is bacitracin usually used clinically?

Used TOPICALLY for:

• Skin infections

• Wounds

• Surface lesions

• Mucous membranes

Why is topical bacitracin useful?

Because it suppresses:

• Mixed bacterial flora
  on skin and wounds.

Cephalosporins

1st-generation

cefazolin, Cephalexin

penicillin Gsubstitutes.

• Resistant to the staphylococcal penicillinase (including MSSA)

Cephalosporins

2nd-generation

(Cefuroxime, cefotetan, cefoxitin)

Cefotetan and cefoxitin are the only cephalosporins against gram-negative anaerobic bacteria

Cephalosporins

3rd-generation

Cefotaxime, ceftriaxone, ceftazidime

Cephalosporins

4th-generation

Cefepime

Must be administered parenterally.

Effective against aerobic gram-negative organisms, such as Enterobacter species, E. coli, K. pneumoniae, P. mirabilis, P. aeruginos

Cephalosporins

Advanced generation

Ceftaroline

Administered IV as a prodrug

Against MRSA and treat complicated skin and skin structure infections and community-acquired pneumonia

coverage include P. aeruginosa, extendedspectrum β-lactamase (ESBL)-producing Enterobacteriaceae, and Acinetobacter baumannii.

Therapeutic advantage if each cephalosporins

Ceftriaxone(3rd)

longest half life

effective against Neisserisa gonorrhoeae

excreted via bile maybe be used for renal insufficiency

why resistance to penicillin =resistant to cephalosporins

cephalosporins susceptible to extended-spectrum β-lactamases (ESBLs) by E. coli and K. pneumoniae

Cephalosporins has a good or poor oral absorption?

poor (need IV or IM)

Distribution of cephalosporins

Distribute very well

Ceftriaxone, cefotaxime (3 rd gen)] are effective to treat neonatal and childhood meningitis caused by H. influenzae.

Cefazolin (1 st gen)- single prophylaxis dose prior to surgery including orthopedic surgery

Cephalosporins

Elimination

Tubular secretion(doses adjustment is needed for renal impaired patients)

Only ceftriaxone (3 rd gen)is excreted through the bile (can be employed in patients with renal insufficiency)

Cephalosporins

Adverse effects

anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, and hemolytic anemia

Cephalosporins that contain a methylthiotetrazole group (cefamandole, cefmetazole, cefotetan, cefoperazone) cause hypoprothrombinemia (inhibits vitamin K epoxide reductase) and inhibition of aldehyde dehydrogenase like disulfiram .

5th generation cephalosporin-Ceftobiprole

IV injection(prodrug)

Indication: Community and hospital acquired pneumonia

Excreted via the kidney

Common side effects: Nausea, vomiting, dysgeusia(impairment of your sense of taste.)

5th generation cephalosporin-Ceftobiprole

Coverage:

Gram +ve: Staphylococci (MRSA), Vancomycin RA

Gram –ve: Similar to ceftriaxone and ceftazidime (not active against ESBL and carbapenemases strains)

Carbapenems(Imipenem, Meropenem, Doripenem, Ertapenem)

Can treat ESBL-producing bacteria (E.g.: E. coli and K. pneumoniae).

Lacks coverage against P. aeruginosa, Enterococcus species, and Acinetobacter species.

Imipenem resists hydrolysis by most β lactamases

but not the metallo-βlactamases

Why is cilastatin only combined with imipenem?

Cilastatin prevent imipenem from broken down by Inhibiting dehydropeptidase

Which carbapenem penetrates CSF well and is useful in meningitis?

Meropenem

but Imipenem/cilastatin can also penetrate well into body tissues and fluids Including CSF

How are carbapenems eliminated?

Mainly by:

• Glomerular filtration (renal excretion)

Clinical significance:

• Dose adjustment needed in renal impairment

What are the common adverse effects of carbapenems?

Common:

• Nausea

• Vomiting

• Diarrhoea

Less common:

• Eosinophilia-abnormally high count of eosinophils (a type of white blood cell) in the blood

• Neutropenia-a condition characterized by a lower-than-normal level of neutrophils,

Which carbapenem is most associated with seizures?

Imipenem

Especially:

• High doses

• Renal impairment

Meropenem has lower seizure risk.

What is the main monobactam antibiotic?

Aztreonam

Route:

• IV

• IM

What is unique about the β-lactam ring in monobactams?

The β-lactam ring is:

• NOT fused to another ring

This distinguishes monobactams from:

• Penicillins

• Cephalosporins

• Carbapenems

What bacteria does aztreonam mainly cover?

Strong activity against:

• Gram-negative bacteria

Especially:

• Enterobacteriaceae

• Pseudomonas aeruginosa

What organisms are NOT covered by aztreonam?

Aztreonam lacks activity against:

• Gram-positive bacteria

• Anaerobes

Mnemonic:
“Aztreonam = NEGATIVE only”

How does aztreonam work?

Mechanism of action:

• Binds to PBPs

• Inhibits bacterial cell wall synthesis

• Prevents peptidoglycan cross-linking

Result:
→ Bacterial death (bactericidal)

Is aztreonam resistant to β-lactamases?

Yes

Aztreonam is resistant to:

• Most β-lactamases

BUT:

• Can be destroyed by ESBLs

(Extended-spectrum β-lactamases)

What important pharmacokinetic property does aztreonam have?

Aztreonam can accumulate in:

• Renal failure patients

Therefore:

• Dose adjustment is needed in renal impairment

What are the adverse effects of aztreonam?

Generally nontoxic

Possible side effects:

• Phlebitis

• Skin rash

• Abnormal liver function tests

Why is aztreonam useful in β-lactam allergic patients?

Because it has:

• Little cross-reactivity with other β-lactams

Can be used in patients allergic to:

• Penicillins

• Cephalosporins

• Carbapenems

High-yield summary of aztreonam?

Aztreonam is a monobactam active mainly against gram-negative bacteria including Pseudomonas, resistant to many β-lactamases, and useful in β-lactam-allergic patients.

Gram (+ve) Physical properties

peptidoglycan layer is much thicker in grampositive than in gram-negative

Penicillin-binding proteins (PBPs) are membrane proteins that cross-link peptidoglycan.

TRUE/FALSE

True

Cell wall inhibitors work on actively proliferating microorganisms (no effect on bacteria that are not growing and dividing)

True/false

True

Characteristic of Penicillin?

widely effective and least toxic

Note: Penicillins

Penicillins are only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall

(inactive against mycobacteria, protozoa, fungi, and viruses).

MOA of penicillin(2)

1.Inhibit PBP

2.Production of autolysins

MOA of penicillin for inhibit PBP?detailed

1. Bacterial cell wall consists of strands of repeating (NAG) and (NAM) subunits. The NAM subunits have short peptide chains (used in cross-linking).

2. The penicillin binding protein (PBP) forms a crosslink

3. The PBP dissociates from the wall once the cross-link has been formed.

4. Penicillin is added to the system. It enters the active site of the PBP and reacts with the serine group.

5. The beta-lactam ring of penicillin covalently linked to the PBP and permanently blocks the active site.

Thus blocking cross linking of peptidoglycan