Second generation cephalosporins

Second-generation cephalosporins are beta-lactam antibiotics that belong to the broader cephalosporin family, which are semisynthetic derivatives of the natural compound cephalosporin C. These antibiotics are classified based on their antibacterial spectrum and pharmacokinetic properties into five generations. Second-generation cephalosporins were developed to improve upon the limited gram-negative coverage of first-generation cephalosporins while maintaining reasonable gram-positive activity.

They are more stable to beta-lactamases produced by certain gram-negative organisms and have better penetration into tissues and fluids, including respiratory tract secretions and some CNS compartments. As such, they are frequently used in the management of respiratory tract infections, skin and soft tissue infections, urinary tract infections, pelvic inflammatory disease, and surgical prophylaxis.

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1. Chemical and Structural Characteristics

Second-generation cephalosporins share a core beta-lactam ring structure, but differ from first-generation cephalosporins by the presence of additional side chains that enhance:

• Stability against hydrolysis by certain beta-lactamases (not ESBLs or AmpC)

• Gram-negative bacterial cell wall penetration

• Broader spectrum of activity compared to first-generation agents

Some second-generation cephalosporins contain a methoxyimino group, which imparts enhanced resistance to beta-lactamase degradation (e.g., cefuroxime).

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2. Mechanism of Action

Second-generation cephalosporins function by inhibiting bacterial cell wall synthesis. They bind to penicillin-binding proteins (PBPs) located within the bacterial cell membrane, which are essential for the final stages of peptidoglycan cross-linking. This results in:

• Disruption of cell wall integrity

• Cell lysis and death (bactericidal activity)

They are time-dependent antibiotics, meaning their efficacy is dependent on the duration of time the drug concentration remains above the minimum inhibitory concentration (MIC).

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3. Spectrum of Activity

Second-generation cephalosporins exhibit broader gram-negative coverage than first-generation agents and retain moderate gram-positive activity. However, they are less active against Staphylococcus aureus (especially MRSA) than first-generation agents and lack activity against Pseudomonas aeruginosa.

Gram-Positive Bacteria (moderate activity)

• Streptococcus pneumoniae

• Streptococcus pyogenes (Group A)

• Staphylococcus aureus (methicillin-sensitive only)

Gram-Negative Bacteria (enhanced activity)

• Haemophilus influenzae

• Moraxella catarrhalis

• Escherichia coli

• Klebsiella pneumoniae

• Proteus mirabilis

• Neisseria gonorrhoeae (cefuroxime, cefaclor)

Anaerobes (limited or variable)

• Bacteroides fragilis (cefoxitin, cefotetan only)

• Clostridium spp. (non-difficile strains)

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4. Classification: Oral vs. Parenteral Agents

A. Oral Second-Generation Cephalosporins

These agents are suitable for mild to moderate outpatient infections.

1. Cefuroxime axetil

   • Prodrug of cefuroxime; acid-stable

   • Indications: Otitis media, sinusitis, bronchitis, Lyme disease, pharyngitis

   • Spectrum: Covers beta-lactamase–producing H. influenzae and M. catarrhalis

2. Cefaclor

   • Indications: Pharyngitis, otitis media, skin infections

   • Acid-labile; taken with food improves absorption

   • Less beta-lactamase resistant than cefuroxime

3. Loracarbef (discontinued in many markets)

   • Carbacephem class; similar to cefaclor

   • Indications: Similar to cefaclor

B. Parenteral Second-Generation Cephalosporins

Used in more serious or hospital-acquired infections and perioperative prophylaxis.

1. Cefuroxime sodium

   • IV/IM formulation

   • Indications: Pneumonia, septicemia, meningitis (limited), surgical prophylaxis

   • Stable against many beta-lactamases

2. Cefoxitin

   • A cephamycin subgroup of second-generation

   • Broad anaerobic coverage

   • Indications: Intra-abdominal infections, PID, colorectal surgical prophylaxis

3. Cefotetan

   • Also a cephamycin

   • Long half-life (~4 hours)

   • Indications: Pelvic inflammatory disease, GI surgical prophylaxis, mixed infections

   • Disulfiram-like reaction with alcohol due to MTT side chain

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5. Pharmacokinetics

Drug	Bioavailability	Half-Life	Route	Renal Excretion	CSF Penetration
Cefuroxime axetil	~37–52%	1–1.5 h	Oral	Yes	No
Cefaclor	~90%	0.5–1 h	Oral	Yes	No
Cefuroxime sodium	—	1.1–1.5 h	IV/IM	Yes	Partial
Cefoxitin	—	~0.8–1 h	IV/IM	Yes	Poor
Cefotetan	—	~4 h	IV/IM	Yes	No

6. Clinical Indications

A. Respiratory Tract Infections

• Acute bacterial sinusitis

• Acute otitis media

• Community-acquired pneumonia (CAP)

• Bronchitis (acute and chronic exacerbations)

B. Skin and Soft Tissue Infections

• Uncomplicated cellulitis

• Impetigo

• Infected wounds

C. Genitourinary Infections

• Uncomplicated UTIs

• Acute pyelonephritis

• Epididymitis

D. Gynecologic and Abdominal Infections

• Pelvic inflammatory disease (PID) – Cefoxitin + doxycycline

• Intra-abdominal infections with anaerobes – Cefoxitin, Cefotetan

• Surgical prophylaxis – especially colorectal and gynecologic procedures

E. Lyme Disease

• Early Lyme borreliosis (cefuroxime as an oral alternative to doxycycline)

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7. Adverse Effects

Category	Details
Hypersensitivity	Rash, urticaria, anaphylaxis (cross-reactivity with penicillins ~1–10%)
Gastrointestinal	Diarrhea, nausea, vomiting, Clostridioides difficile-associated colitis
Hematologic	Eosinophilia, thrombocytopenia, leukopenia (rare)
Renal	Interstitial nephritis (rare)
Hepatic	Mild transaminase elevations
Others	Disulfiram-like reaction (cefotetan), hypoprothrombinemia

8. Drug Interactions

Drug/Agent	Interaction	Mechanism
Probenecid	Increases cephalosporin levels	Competes for renal tubular secretion
Warfarin	↑ INR with cefotetan	Hypoprothrombinemia due to MTT side chain
Alcohol	Avoid with cefotetan	Disulfiram-like reaction
Aminoglycosides	↑ Nephrotoxicity risk	Additive toxicity to renal tubules

9. Resistance Mechanisms

Second-generation cephalosporins are susceptible to resistance through:

• Beta-lactamase production: Especially extended-spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases

• Altered penicillin-binding proteins (PBPs): As seen in Streptococcus pneumoniae

• Efflux pumps and porin channel mutations in gram-negative bacteria

They lack activity against:

• Pseudomonas aeruginosa

• MRSA

• ESBL-producing Enterobacteriaceae

• Enterococcus faecalis/faecium

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10. Dosing Overview

Drug	Usual Adult Dose	Frequency
Cefuroxime axetil	250–500 mg orally	Every 12 h
Cefaclor	250–500 mg orally	Every 8 h
Cefuroxime (IV)	750–1500 mg IV/IM	Every 8 h
Cefoxitin (IV)	1–2 g IV	Every 6–8 h
Cefotetan (IV)	1–2 g IV	Every 12 h

Renal dose adjustments are required in moderate to severe renal impairment.

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11. Summary of Generic and Brand Names

Generic Name	Common Brand Names	Route
Cefuroxime axetil	Zinacef (IV), Ceftin (oral)	Oral/IV
Cefaclor	Ceclor	Oral
Cefoxitin	Mefoxin	IV
Cefotetan	Cefotan	IV
Cefuroxime sodium	Zinacef	IV/IM

12. Role in Clinical Guidelines

• IDSA guidelines for CAP (2021): Cefuroxime is an oral beta-lactam alternative to amoxicillin-clavulanate for outpatient pneumonia treatment

• CDC PID treatment guidelines: Cefoxitin used in combination therapy with doxycycline

• Surgical prophylaxis guidelines: Cefoxitin or cefotetan for abdominal and gynecologic procedures

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13. Comparison with First and Third Generations

Feature	1st Gen (e.g., cefazolin)	2nd Gen (e.g., cefuroxime)	3rd Gen (e.g., ceftriaxone)
Gram-positive coverage	Excellent	Moderate	Good
Gram-negative coverage	Limited	Moderate	Enhanced
Anaerobic activity	None	Cefoxitin, cefotetan only	Minimal
CNS penetration	Poor	Variable	Good (ceftriaxone, cefotaxime)
Pseudomonas coverage	No	No	Only ceftazidime among 3rd-gen