W11 Antibacterials 2

What are the 5 major antibacterial drug classes?

Cell Wall Synthesis Inhibitors, Cell Membrane Disruptors, Folate Synthesis Inhibitors, Protein Synthesis Inhibitors, DNA Synthesis Inhibitors

What are the two subclasses of Cell Wall Synthesis Inhibitors?

β-lactams (Penicillins, Cephalosporins, Carbapenems) and Glycopeptides (Vancomycin)

What class do Polymyxins belong to?

Cell Membrane Disruptors

What two drugs make up the Folate Synthesis Inhibitor class?

Sulfonamides and Trimethoprim

What drug class acts as a DNA Synthesis Inhibitor?

Fluoroquinolones

Do human beings synthesize their own folic acid?

No — humans absorb folic acid from the diet only; prokaryotes (bacteria) synthesize their own folic acid

Why is targeting folic acid synthesis an example of selective toxicity?

Because only prokaryotes synthesize their own folic acid; humans get it from food, so inhibiting folate synthesis harms only bacteria and not host cells

What are the two forms of folic acid?

Dihydrofolic acid (DHF) and Tetrahydrofolic acid (THF)

What is the precursor for folic acid synthesis in prokaryotic (bacterial) cells?

P-aminobenzoic acid (PABA) + pteridine

What are folates required for in bacterial cells?

DNA synthesis (specifically purine synthesis)

What is the complete pathway of folate synthesis in bacteria?

PABA → (Dihydropteroate synthase) → Dihydrofolate → (Dihydrofolate reductase) → Tetrahydrofolate → Purines → DNA

What are the two enzymes involved in bacterial folate synthesis?

1) Dihydropteroate synthase (converts PABA → Dihydrofolate) and 2) Dihydrofolate reductase (converts Dihydrofolate → Tetrahydrofolate)

Which enzyme do Sulfonamides inhibit?

Dihydropteroate synthase (DHPS) (blocking conversion of PABA → Dihydrofolate) (DHPS)

Which enzyme does Trimethoprim inhibit?

Dihydrofolate reductase (DHFR) (blocking conversion of Dihydrofolate → Tetrahydrofolate)

How do Sulfonamides compete at the level of Dihydropteroate synthase?

They are structural analogs of PABA and competitively inhibit Dihydropteroate synthase

What is the brand name for the combination of Sulfamethoxazole + Trimethoprim?

Bactrim® (also called Cotrimoxazole)

What are the two clinical advantages of combining SMX and TMP (Cotrimoxazole)?

1) Synergistic effects — blocks two sequential steps in the same pathway; 2) Making it more effective against resistant strains

What is the ratio of SMX to TMP in Cotrimoxazole (Bactrim®)?

5:1 (SMX:TMP)

What are the indications for SMX-TMP?

Used to treat infections caused by both gram +ve and gram -ve bacteria, commonly used in treating pulmonary and urinary tract infections

How is Cotrimoxazole (SMX-TMP) excreted from the body?

In the urine (renal excretion)

What adverse effects can result from Cotrimoxazole's (SMX-TMP) renal excretion?

Crystalluria — crystals forming in the urine; patients should be advised to drink plenty of water and Sula drug allergy. Also: Hyperkalemia, hyponatremia, thrombocytopenia, folic acid deficiency in elederly

In which patient population are Cotrimoxazole ADRs most commonly and severely seen?

AIDS patients (because they often have compromised renal function, reduced hydration, and immune dysregulation)

Which drugs should be avoided when a patient is on Cotrimoxazole due to drug interactions?

Bacterial live attenuated vaccines (the antibacterial effect can kill the live attenuated bacteria in the vaccine)

What is the ribosome composition of eukaryotic cells?

80S ribosome composed of 60S and 40S subunits

What is the ribosome composition of prokaryotic (bacterial) cells?

70S ribosome composed of 50S and 30S subunits

Why can protein synthesis inhibitors achieve selective toxicity?

Because they target the bacterial 70S ribosome (specifically 30S or 50S subunits), which differs structurally from the eukaryotic 80S ribosome

What is the mnemonic for protein synthesis inhibitors and their ribosomal subunit targets?

Buy AT 30, CELL AT 50 → AT 30S: Aminoglycosides, Tetracyclines; CELL 50S: Chloramphenicol (C), Erythromycin/Macrolides (E), Linezolid (L), Clindamycin (L)

What is the MOA of Aminoglycosides?

Inhibit ribosomal 30S subunit and inhibit synthesis in bacterial cells.

What are the five common drug members of the Aminoglycoside class?

Gentamicin, Amikacin, Streptomycin, Kanamycin, Tobramycin (mnemonic: "Get A Stick, Kill Tom") commonly have the suffix -mycin

What is the indication for Aminoglycosides specifically?

Reserved for serious gram-positive and gram-negative infections; Streptomycin is used in tuberculosis (TB) when other anti-TB agents are contraindicated

What are the four ADRs associated with Aminoglycosides and what is the mnemonic?

Neurotoxicity, Nephrotoxicity, Ototoxicity, Teratogenicity — mnemonic: NNOT. Important to monitor serum concentrations and avoid concomitant use of drugs that cause these effects

Why must Aminoglycosides be used with caution in pregnant patients?

They are teratogenic — they can cause fetal harm including irreversible ototoxicity in the developing fetus

Which ribosomal subunit do Tetracyclines target?

30S (inhibit protein synthesis)

What is the main example of a Tetracycline antibiotic?

Doxycycline. Also : tetracyclin, minocycline, demeclocycline

What are the clinical indications for Doxycyclines?

1) Broad-spectrum: gram-positive and gram-negative infections (all tetracyclines) ; 2) Prophylaxis of malaria (in areas having chloroquine- and/or pyrimethamine-sulfadoxine-resistant strains.

What is the key ADR associated with Tetracyclines in children?

Permanent discoloration of teeth (yellow, gray, or brown staining) due to chelation with calcium in developing teeth — occurs with in utero or childhood exposure - and is more likely to occur follwoing long-term or repeated exposure; intracranial hypertension; tissue hyperpigmentation; photosensitivity.

Why do Tetracyclines cause tooth discoloration?

Tetracycline chelates with Ca²⁺ (calcium ions) and deposits in developing teeth and bones, causing permanent discoloration

In which patient populations should Tetracyclines be avoided due to tooth discoloration risk?

Pregnant women (in utero exposure) and children under 8 years old

What are some DIs associated with Tetracyclines?

Antacids, bacterial vaccines, dairy products

Which ribosomal subunit do Macrolides target?

50S

What are some examples of drugs that are a member of the Macrolides class?

Azithromycin, Erythromycin , clarithromycin, fidaxomicin (suffix: "-thromycin")

What are the clinical indications for Macrolides?

Broad-spectrum gram-positive and gram-negative infections, chlamydia infections; Azithrimycin is the first-line for community-acquired pneumonia (bacterial)

What are the ADRs associated with Macrolides?

QTc prolongation,hepatotoxicity, infantile hypertrophic pyloric stenosis, myasthenia gravis exacerbation, C. difficile-associated diarrhea

What drug interactions are clinically important with Macrolides?

QTc-prolonging drugs (risk of Torsades de Pointes) and bacterial live attenuated vaccines

What is the MOA of Oxazolidinones?

Inhibit protein synthesis by binding at the P site at the 50S ribosomal subunit.

What are some examples of Oxazolidinones?

Linezolid and tedizolid

What is the clinical indication for Oxazolidinones (Linezolid)?

Gram-positive infections, including drug-resistant organisms like MRSA and VRE (Vancomycin-Resistant Enterococcus faecium). Linezolid is bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci.

What are the ADRs/warnings/precautions associated with Oxazolidinones (Linezolid)?

Use with caution in pateints with myelosuppression, hypertension, seizures, diabetes; may cause hematologic abnormalities.

What are the DIs associated with Oxazolidinones(Linezolid)?

MAOIs, bacterial vaccines, serotonin modulators, opiods

What are the three drugs that can be used to treat MRSA infections?

1) Linezolid (Oxazolidinone), 2) Vancomycin (Glycopeptide), 3) Ceftaroline (5th generation cephalosporin)

Which ribosomal subunit do Lincosamides target?

50S

What is the main example of a Lincosamide antibiotic?

Clindamycin (also lincomycin)

What are the clinical indications for Lincosamides (Clindamycin)?

Reserved for serious infections - infections caused by both gram +ve and gram -ve bacteria and anaerobes; and alternative for penicillin-allergic patients

Why are Lincosamides NOT suitable for CNS infections?

Because Clindamycin does not cross the blood-brain barrier (BBB)

What ADR is uniquely associated with Lincosamides in infants?

Gasping syndrome — characterized by severe respiratory distress in neonates/infants due to the benzyl alcohol present in the formulation

Whar are some other ADRs associated with Lincosamides?

Hypotension (rare with IV), thrombophlebitis and metallic taste

What drug interactions are important clinically with Lincosamides?

Neuromuscular blockers — Lincosamides can prolong their action, increasing the risk of prolonged paralysis. Also bacterial vaccines

What is the mechanism of action (MoA) of Fluoroquinolones?

They inhibit bacterial Topoisomerase II (DNA gyrase) and Topoisomerase IV — both Type II topoisomerases — which are required for DNA replication, transcription, repair, and recombination. (DNA synthesis inhibitors)

What are the common Fluoroquinolone drug members?

Ciprofloxacin, Levofloxacin, moxifloxacin, gemifloxacin (respiratory FQs)

What are the indications for Flouroquinolones use?

Gram +ve and gram -ve infections

Whar are the ADRs associated wih Fluoroquinolone use?

Diarrhea, abnormal LFT, tendon damage, insomnia, dizziness, GI disturbances

What are the boxed warnings for Fluoroquinolones?

Tendinitis and tendon rupture (most notably affecting the Achilles tendon), peripheral neuropathy, and CNS effect; exacerbate myasthenia gravis

Which patient population is at highest risk of Fluoroquinolone-induced tendon rupture?

Elderly patients and those on concomitant corticosteroids

Antibacterial suffixes

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Why is Ciprofloxacin used for prostatitis?

It is a fluoroquinolone with excellent tissue penetration (including the prostate) and good gram-negative coverage, making it effective for this condition

A 70-year-old man with bacterial endocarditis starts Gentamicin therapy. Which ADR is he most at risk for?

Hearing loss (Ototoxicity) — Gentamicin is an Aminoglycoside, and Aminoglycosides carry the ADR mnemonic NNOT: Neurotoxicity, Nephrotoxicity, Ototoxicity, Teratogenicity

An 18-year-old woman has diffuse brownish-yellow discoloration of all teeth with no current medication use. What was the most likely cause during her childhood?

Tetracycline use — Tetracyclines chelate with Ca²⁺ in developing teeth and bones, causing permanent discoloration

A 35-year-old male sprinter allergic to sulfa drugs is prescribed an antibiotic for prostatitis. He returns 3 weeks later with severe bilateral foot tendon pain. Which drug was prescribed?

Ciprofloxacin — a Fluoroquinolone with the ADR of tendinitis and tendon rupture; sulfa allergy ruled out TMP+SMZ

A 28-year-old woman with recurrent UTIs needs a broad-spectrum antibiotic. Which drug causes discoloration of teeth and should be avoided in children?

Doxycycline (a Tetracycline) — causes permanent tooth discoloration through Ca²⁺ chelation; contraindicated in children

An AIDS patient with bacterial pneumonia needs an antibiotic combination that can cause crystalluria. Which combination is this?

TMP+SMZ (Cotrimoxazole) — excreted in urine, can crystallize especially in dehydrated patients; AIDS patients are particularly susceptible to ADRs

A 42-year-old penicillin-allergic patient needs treatment for community-acquired pneumonia with a drug effective against both gram-positive and gram-negative bacteria. Which antibiotic is best?

Azithromycin — a Macrolide that is broad-spectrum (gm+/-) and the first-line drug for community-acquired pneumonia; safe in penicillin-allergic patients

A 55-year-old woman with a serious MRSA skin infection needs treatment. Which of these is NOT appropriate for MRSA: Linezolid, Vancomycin, Ceftaroline, or Azithromycin?

Azithromycin — it is a Macrolide effective against a broad range of bacteria but is NOT among the drugs used for MRSA. Linezolid, Vancomycin, and Ceftaroline are the appropriate choices

A tuberculosis patient needs an antibiotic targeting the 30S ribosomal subunit. Which is most appropriate?

Streptomycin — an Aminoglycoside that targets the 30S subunit and is used in TB when other anti-TB agents are contraindicated

Which antibiotic class is known for causing QTc prolongation and should be used cautiously in patients with pre-existing heart conditions?

Macrolides (e.g., Azithromycin) — they cause QTc prolongation, increasing the risk of arrhythmias especially Torsades de Pointes

A newborn with a severe infection needs antibiotic therapy. Which antibiotic associated with "gasping syndrome" must be avoided?

Clindamycin (a Lincosamide) — associated with gasping syndrome (severe respiratory distress) in neonates and infants

A patient needs an antibiotic that inhibits Dihydropteroate synthase. Which drug specifically inhibits this enzyme?

Sulfamethoxazole (SMX) — the sulfonamide component of Cotrimoxazole (Bactrim) inhibits Dihydropteroate synthase, blocking PABA →no Dihydrofolate conversion

A patient at risk of both nephrotoxicity and ototoxicity is being prescribed antibiotics. Which drug must be prescribed with great caution?

Gentamicin (Aminoglycoside) — known for nephrotoxic and ototoxic potential; requires monitoring of kidney function and hearing

A patient needs both malaria prophylaxis and a broad-spectrum antibiotic. Which single drug serves both purposes?

Doxycycline — it is a broad-spectrum tetracycline AND a prophylactic agent against malaria (including chloroquine-resistant Plasmodium falciparum)

Why is Linezolid specifically useful for VRE infections?

Linezolid (Oxazolidinone) targets the 50S ribosomal subunit and has activity against gram-positive organisms including VRE (Vancomycin-Resistant Enterococcus faecium), bypassing the vancomycin resistance mechanism

What is the clinical significance of Fluoroquinolones inhibiting both DNA gyrase and Topoisomerase IV?

Inhibiting both enzymes simultaneously makes resistance development harder and ensures broader bactericidal activity — Topoisomerase II (gyrase) mainly acts in gram-negative bacteria while Topoisomerase IV is more important in gram-positive bacteria

Which Aminoglycoside is most commonly used for gram-negative serious infections such as sepsis and which one is reserved for TB?

Gentamicin/Amikacin/Tobramycin for serious gram-negative infections; Streptomycin is reserved specifically for tuberculosis when other anti-TB agents are contraindicated

What is the difference in gram coverage between Linezolid (Oxazolidinone) and Macrolides?

Linezolid covers only gram-positive organisms (gm+); Macrolides cover both gram-positive and gram-negative organisms (gm+/-)

What makes Ceftaroline unique among cephalosporins in treating MRSA?

Ceftaroline is a 5th-generation cephalosporin — the only cephalosporin with activity against MRSA, making it an exception to the general rule that β-lactams cannot treat MRSA

Why is "gasping syndrome" a unique concern with Clindamycin in neonates?

Neonates have immature liver function and cannot metabolize the benzyl alcohol preservative found in some Clindamycin formulations, leading to metabolic acidosis and respiratory failure ("gasping syndrome")

What is the clinical significance of Lincosamides prolonging neuromuscular blocker action?

If a patient on Clindamycin is given neuromuscular blockers (e.g., during surgery), the duration of paralysis may be prolonged, potentially causing respiratory failure in the postoperative period

Why are Aminoglycosides described as bactericidal rather than bacteriostatic?

They irreversibly bind the 30S ribosomal subunit, causing misreading of mRNA and production of aberrant proteins, which disrupts cell membrane integrity leading to cell death — a bactericidal mechanism

What is community-acquired pneumonia (CAP) and which antibacterial class + specific drug is preferred?

CAP is pneumonia acquired outside a hospital setting; Azithromycin (a Macrolide) is the preferred drug due to its broad-spectrum (gm+/-) coverage and excellent lung tissue penetration