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Cephalosporins - Complete Exam Guide

What Are Cephalosporins?

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Mechanism of Action

1. Binding to Penicillin-Binding Proteins (PBPs) - These serve as drug receptors on the bacterial cell membrane.
2. Inhibiting transpeptidation - Blocking cross-linking of peptidoglycan strands, preventing cell wall synthesis.
3. Activating autolytic enzymes - Triggering bacterial autolysins that create lethal lesions in the cell wall.

Result: Bactericidal activity against susceptible organisms.

• Enterococci (lack essential PBP binding)
• MRSA (low-affinity PBP2a)
• Listeria monocytogenes
• Atypicals (Mycoplasma, Chlamydia, Legionella)

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Classification by Generation

First Generation

1. Surgical prophylaxis (cefazolin - first choice)
2. Skin and soft tissue infections / UTI (cephalexin)

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Second Generation

1. Intra-abdominal / pelvic infections (cefoxitin, cefotetan - due to B. fragilis coverage)
2. Upper respiratory tract infections (cefuroxime - otitis media, sinusitis, community-acquired pneumonia)

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Third Generation

1. Bacterial meningitis (ceftriaxone or cefotaxime - excellent CNS penetration)
2. Community-acquired pneumonia / gonorrhea / pyelonephritis (ceftriaxone)

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Fourth Generation

1. Febrile neutropenia / hospital-acquired infections
2. Pseudomonas aeruginosa infections (especially in ICU/immunocompromised)

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Fifth Generation (Anti-MRSA Cephalosporins)

1. MRSA infections (skin/soft tissue, pneumonia)
2. Community-acquired bacterial pneumonia

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Novel/Combination Agents

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Adverse Effects

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Quick Memory Aid - Spectrum by Generation

1st Gen → Gram (+) dominant (Skin, surgical prophylaxis)
2nd Gen → ↑ Gram (−), adds anaerobes (Abdominal, respiratory)
3rd Gen → Gram (−) dominant, CNS penetration (Meningitis, gonorrhea)
4th Gen → Broadest stable spectrum (Pseudomonas + ICU infections)
5th Gen → MRSA active

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Mechanisms of Resistance

1. Beta-lactamase production - Enzymatic hydrolysis of the beta-lactam ring (most common)
2. Altered PBPs - Decreased affinity (e.g., PBP2a in MRSA, altered PBP1A/2X in resistant pneumococci)
3. Reduced permeability - Porin loss in Gram-negative bacteria
4. Efflux pumps - Active drug expulsion

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Aminoglycosides - Uses & Adverse Effects (Exam Guide)

Members / Classification

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Mechanism of Action

1. Passive diffusion through porin channels in the outer membrane (Gram-negatives)
2. Active transport across the cytoplasmic membrane via an oxygen-dependent, proton pump-coupled process (this is why anaerobes are intrinsically resistant)
3. Binding to 30S ribosomal subunit - causes:
   • Interference with formation of the initiation complex
   • Misreading of mRNA → incorporation of wrong amino acids → non-functional proteins
   • Breakup of polysomes into non-functional monosomes

Result: Bactericidal, concentration-dependent killing (higher peak = better kill)

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Spectrum of Activity

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Clinical Uses

1. Serious Gram-Negative Infections (with beta-lactam)

• Sepsis / bacteremia from Gram-negative organisms (gentamicin or amikacin + beta-lactam)
• Hospital-acquired pneumonia (especially Pseudomonas - tobramycin or amikacin)
• Complicated UTI / pyelonephritis (gentamicin)
• Febrile neutropenia (empiric, combination therapy)

2. Infective Endocarditis (Synergy Regimens)

• Enterococcal endocarditis: Gentamicin or streptomycin + ampicillin or vancomycin
• Streptococcal endocarditis: Low-dose gentamicin + penicillin (shorter course)
• Staphylococcal prosthetic valve endocarditis: Gentamicin + anti-staphylococcal penicillin + rifampin

3. Tuberculosis (Streptomycin)

• Second-line TB drug - used in drug-resistant TB (MDR-TB) regimens

4. Cystic Fibrosis

• Inhaled tobramycin (TOBI) or amikacin liposomal inhalation - chronic suppression of Pseudomonas in CF lungs

5. Pelvic Inflammatory Disease / Intra-abdominal Infections

• Gentamicin + clindamycin (classical combination for PID and post-surgical infections)

6. Perioperative / Ocular

• Neomycin: Topical antibiotic (eye drops, ear drops, skin preparations); oral pre-op bowel decontamination
• Gentamicin eye drops: Gram-negative conjunctivitis

7. Plague, Tularemia, Brucellosis

• Streptomycin or gentamicin

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Adverse Effects

1. Nephrotoxicity ⚠️ (Most Common)

• Cationic amino groups on the drug bind to anionic megalin on the brush border of proximal tubule cells
• Endocytosis causes drug accumulation in lysosomes at 100-1000x serum concentration
• Impairs mitochondrial energetics, phospholipases, and causes oxidative stress

• Non-oliguric AKI appearing after 5-10 days of therapy
• Distal tubule involvement: polyuria, K+ and Mg2+ wasting (hypokalemia, hypomagnesemia)
• Injury can occur even after drug is stopped (lysosomes slowly release drug)

• Prolonged therapy, high daily dose
• Pre-existing renal disease, advanced age
• Hypovolemia / hypotension
• Concurrent nephrotoxins (especially vancomycin - synergistic nephrotoxicity)
• Sepsis, liver disease

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2. Ototoxicity ⚠️ (Irreversible)

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3. Neuromuscular Blockade (Rare but Life-threatening)

• Myasthenia gravis
• Concurrent neuromuscular blockers (succinylcholine, curare)
• Calcium deficiency / hypomagnesemia

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4. Other Adverse Effects

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Therapeutic Drug Monitoring (TDM) - Exam Points

• Peak (30-60 min post-dose): 5-10 mg/L (gentamicin); higher for severe infections
• Trough (just before next dose): < 2 mg/L (minimize nephrotoxicity)

• Exploits concentration-dependent killing and post-antibiotic effect
• Lower trough → less renal tubule accumulation → less nephrotoxicity
• NOT recommended for enterococcal/streptococcal endocarditis (insufficient data)

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Quick Exam Summary

Mechanism     → Irreversible 30S ribosome inhibitor (bactericidal, concentration-dependent)
Spectrum      → Gram-negative rods + Pseudomonas; synergy with cell-wall drugs for Gram-positives
Key Uses      → Gram-neg sepsis, endocarditis synergy, TB (streptomycin), CF (inhaled tobramycin), PID
Nephrotoxicity → Proximal tubule accumulation; non-oliguric AKI after 5-10 days
Ototoxicity   → Irreversible; cochlear (amikacin) or vestibular (streptomycin/gentamicin)
Potentiated by → Loop diuretics (ototoxicity), vancomycin (nephrotoxicity)
NM blockade   → Rare; IV calcium gluconate reverses it
Avoid in      → Pregnancy, myasthenia gravis, concurrent loop diuretics/nephrotoxins

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⚡ Aminoglycosides - High-Yield Exam Notes

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MEMBERS (Mnemonic: "GNATS KAN")

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MECHANISM

• Inhibit 30S ribosome → irreversible protein synthesis inhibition
• Bactericidal, concentration-dependent
• Require oxygen for transport into cell → anaerobes are resistant
• Synergistic with beta-lactams/vancomycin (cell wall disruption enhances uptake)

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SPECTRUM

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KEY USES

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ADVERSE EFFECTS - THE BIG THREE

1. NEPHROTOXICITY

• Proximal tubule accumulation → non-oliguric AKI after 5-10 days
• Also causes K+ and Mg2+ wasting (hypokalemia, hypomagnesemia)
• Risk increased by: vancomycin, loop diuretics, old age, dehydration, pre-existing renal disease
• Prevention: TDM, once-daily dosing, hydration

2. OTOTOXICITY (Irreversible!)

• Potentiated by: Loop diuretics (furosemide, ethacrynic acid) ← favourite exam Q
• Risk: renal failure (↓ clearance), prolonged high-dose use

3. NEUROMUSCULAR BLOCKADE

• Blocks pre-synaptic ACh release + post-synaptic ACh sensitivity
• Presents as: acute flaccid paralysis, apnea
• Risk: myasthenia gravis, concurrent muscle relaxants, hypocalcemia
• Treatment: IV calcium gluconate ± neostigmine

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OTHER EFFECTS

• Rash (especially neomycin - contact dermatitis)
• Fetal ototoxicity - Category D, avoid in pregnancy
• Oral neomycin → malabsorption syndrome

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MUST-KNOW EXAM POINTS

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RELATIVE TOXICITY

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