First generation cephalosporins

Introduction

First-generation cephalosporins represent the earliest class of cephalosporin antibiotics—semisynthetic β-lactam antimicrobials derived from Cephalosporium acremonium (formerly Acremonium). They exhibit potent bactericidal activity against a broad range of Gram-positive cocci, with modest Gram-negative coverage. These agents are most frequently utilized for skin and soft tissue infections, surgical prophylaxis, and mild respiratory or urinary tract infections where narrow-spectrum therapy is preferred.

Structurally and functionally related to penicillins, first-generation cephalosporins possess the β-lactam ring and exert their effects by disrupting bacterial cell wall synthesis. Despite the emergence of later-generation cephalosporins with broader spectra, the first generation remains clinically relevant due to their high efficacy, low cost, and favorable safety profile.

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1. Drugs Included in the Class

A. Parenteral Agents:

• Cefazolin (the only first-generation cephalosporin used intravenously)

  • Brand names: Ancef, Kefzol

B. Oral Agents:

• Cephalexin

  • Brand names: Keflex, Rilexine

• Cefadroxil

  • Brand names: Duricef, Biodroxil

Other agents like cephradine and cephapirin have been withdrawn or are rarely used today.

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2. Mechanism of Action

First-generation cephalosporins act by inhibiting bacterial cell wall synthesis through binding to penicillin-binding proteins (PBPs). These proteins are essential for the cross-linking of peptidoglycan strands in bacterial cell walls.

The inhibition leads to:

• Disruption of cell wall integrity

• Bacterial lysis via osmotic imbalance

• Bactericidal activity (particularly effective against Gram-positive cocci)

Cephalosporins are resistant to many penicillinases (β-lactamases produced by Gram-positive organisms), but not ESBLs or AmpC β-lactamases.

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3. Antimicrobial Spectrum

A. Gram-Positive Activity (Excellent Coverage)

• Staphylococcus aureus (methicillin-sensitive only – MSSA)

• Staphylococcus epidermidis (MSSA)

• Streptococcus pyogenes (Group A Streptococcus)

• Streptococcus agalactiae (Group B Streptococcus)

• Streptococcus pneumoniae (non-penicillin resistant strains)

• Viridans group streptococci

B. Gram-Negative Activity (Limited Coverage)

• Escherichia coli

• Klebsiella pneumoniae

• Proteus mirabilis

C. Anaerobes

• Poor to no activity

• Not effective against Bacteroides fragilis

D. Not Active Against

• MRSA

• Pseudomonas aeruginosa

• Enterococcus spp.

• Enterobacter spp.

• Serratia spp.

• Acinetobacter spp.

• Neisseria gonorrhoeae

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4. Clinical Indications

Indication	First-Generation Use
Skin and soft tissue infections	Cellulitis, impetigo, infected wounds
Surgical prophylaxis	Especially with cefazolin for clean procedures
Urinary tract infections	Uncomplicated UTI caused by E. coli or P. mirabilis
Upper respiratory infections	Pharyngitis, tonsillitis (when penicillin is not used)
Osteomyelitis	Early MSSA infections (cefazolin IV)
Endocarditis prophylaxis	In selected dental procedures (cephalexin)
Mastitis	Empiric treatment for lactational mastitis

They are not used in serious systemic infections caused by resistant Gram-negatives or in polymicrobial anaerobic infections.

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5. Pharmacokinetics

Parameter	Cefazolin	Cephalexin	Cefadroxil
Route	IV/IM	Oral	Oral
Bioavailability	N/A	~95%	~90%
Half-life	~1.5–2 hours	~0.5–1.2 hours	~1.5 hours
Protein binding	~80%	~15%	~20%
Distribution	Good; does not cross BBB	Good tissue penetration	Similar to cephalexin
Elimination	Renal (unchanged)	Renal (unchanged)	Renal (unchanged)

Cefazolin achieves high tissue levels, making it ideal for perioperative prophylaxis.

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6. Dosage and Administration

Cefazolin (IV):

• Mild to moderate infections: 1 g IV every 8 hours

• Severe infections: 2 g IV every 8 hours

• Surgical prophylaxis: 1–2 g IV 30–60 minutes before incision; repeat if surgery is prolonged

• Renal adjustment required for CrCl <50 mL/min

Cephalexin (Oral):

• Adults: 250–500 mg every 6–12 hours

• Children: 25–50 mg/kg/day in divided doses

• Duration: Usually 5–10 days depending on indication

Cefadroxil (Oral):

• Adults: 500 mg to 1 g once or twice daily

• Children: 30 mg/kg/day in divided doses

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7. Adverse Effects

First-generation cephalosporins are generally well tolerated.

Common Adverse Reactions:

• Gastrointestinal:

  • Nausea

  • Diarrhea

  • Abdominal discomfort

• Hypersensitivity:

  • Rash

  • Urticaria

Rare but Serious:

• Anaphylaxis (cross-reactivity with penicillins estimated at 1–10%)

• Stevens-Johnson syndrome (extremely rare)

• Clostridioides difficile-associated diarrhea

• Eosinophilia

• Neutropenia or thrombocytopenia (with prolonged use)

• Elevated liver enzymes (reversible)

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8. Contraindications

• Known hypersensitivity to cephalosporins or other β-lactam antibiotics

• Prior severe reaction (e.g., anaphylaxis) to penicillins warrants caution or avoidance

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9. Precautions and Monitoring

• Adjust dose in renal impairment to avoid accumulation and neurotoxicity.

• Monitor for signs of hypersensitivity, especially in patients with prior β-lactam reactions.

• Monitor renal function and complete blood count during prolonged therapy.

• Observe for superinfections, including fungal overgrowth or C. difficile colitis.

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10. Drug Interactions

• Probenecid: Competes for renal tubular secretion, increasing cephalosporin levels.

• Aminoglycosides (with cefazolin): May increase nephrotoxicity—use caution.

• Warfarin: Cephalosporins may increase bleeding risk via altered gut flora (vitamin K synthesis).

• Loop diuretics: Concurrent use may elevate nephrotoxicity risk.

• Minimal interaction with CYP enzymes; safe in polypharmacy.

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11. Advantages of First-Generation Cephalosporins

• Effective for MSSA and Streptococcal infections

• Low cost and excellent safety profile

• Stable to many penicillinases produced by Gram-positive bacteria

• Good oral bioavailability (cephalexin, cefadroxil)

• Ideal for surgical prophylaxis (cefazolin)

• Narrower spectrum reduces selective pressure for resistance

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12. Limitations

• Poor activity against Gram-negative bacilli, especially Enterobacter, Pseudomonas, and ESBL-producers

• No activity against anaerobes, MRSA, or atypical pathogens

• Shorter half-life → more frequent dosing for some agents

• Not suitable for meningitis due to poor CSF penetration

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13. Clinical Comparisons

Feature	First Gen (e.g., Cefazolin)	Third Gen (e.g., Ceftriaxone)
Gram-positive	Excellent	Moderate
Gram-negative	Limited	Broad
Pseudomonas	Not covered	Some (e.g., ceftazidime)
MRSA	Not covered	Not covered
CSF penetration	Poor	Good (ceftriaxone, cefotaxime)
Surgical prophylaxis	Yes	Occasionally (not preferred)