Cephalosporins Used in Pediatrics

Select a topic Classification and Spectrum Mechanism of Action Pharmacokinetics Indications and Clinical Use Dosing and Administration Adverse Effects and Management Precautions and Contraindications Resistance Mechanisms Comparison with Other Antibiotics First Gen Cephalosporins Overview Cefazolin Cephalexin Cefadroxil Cephradine Cefapirine Second Generation Cefuroxime Cefprozil Cefaclor Cefoxitin Loracarbef Third Generation Overview Ceftriaxone Cefotaxime Ceftazidime Cefixime Cefpodoxime Ceftibuten Fourth Generation Overview Cefepime Cefpirome Fifth Generation Overview Ceftaroline Ceftobiprole

Classification and Spectrum of Cephalosporins

Cephalosporins are classified into generations based on their antimicrobial spectrum and resistance to beta-lactamases:

Generation	Examples	Spectrum	Key Features
First	Cefazolin, Cephalexin, Cefadroxil	Gram-positive cocci (Streptococcus, Staphylococcus) Limited gram-negative coverage	Good tissue penetration Primarily used for skin and soft tissue infections
Second	Cefuroxime, Cefprozil, Cefaclor	Improved gram-negative coverage Retained gram-positive activity Some anaerobic coverage	Increased stability against beta-lactamases Good penetration into respiratory tract
Third	Ceftriaxone, Cefotaxime, Ceftazidime	Broad gram-negative coverage Variable gram-positive activity Some with anti-pseudomonal activity (e.g., Ceftazidime)	High resistance to beta-lactamases Excellent CSF penetration Extended half-life (especially Ceftriaxone)
Fourth	Cefepime	Extended gram-negative coverage Improved gram-positive activity Anti-pseudomonal activity	Enhanced stability against beta-lactamases Good penetration into CNS
Fifth	Ceftaroline	Broad spectrum including MRSA Activity against resistant gram-positive organisms	Active against many multi-drug resistant organisms Limited use in pediatrics, primarily for complicated skin infections

Clinical Pearl: The spectrum of activity generally broadens with each generation, but gram-positive coverage may decrease in 3rd generation cephalosporins. Always consider local resistance patterns when selecting a cephalosporin.

Mechanism of Action

Cephalosporins are bactericidal antibiotics that inhibit bacterial cell wall synthesis. The mechanism involves:

1. Binding to Penicillin-Binding Proteins (PBPs):
   • Cephalosporins bind to specific PBPs in the bacterial cell wall
   • Different cephalosporins have varying affinities for different PBPs
   • This binding inhibits the cross-linking of peptidoglycan strands
2. Inhibition of Cell Wall Synthesis:
   • Prevents the formation of a stable cell wall
   • Results in a weakened bacterial cell structure
3. Activation of Autolytic Enzymes:
   • Triggers the release of bacterial autolysins
   • These enzymes further break down the cell wall
4. Bacterial Cell Lysis:
   • The weakened cell wall cannot withstand osmotic pressure
   • This leads to cell lysis and death

Molecular Basis: The beta-lactam ring of cephalosporins is structurally similar to the D-alanyl-D-alanine terminus of the peptidoglycan precursor. This similarity allows cephalosporins to competitively inhibit the transpeptidase enzymes (PBPs) involved in cell wall synthesis.

Clinical Implications:

• Cephalosporins are most effective against actively dividing bacteria
• They exhibit time-dependent killing, meaning that maintaining concentrations above the MIC is more important than achieving high peak levels
• The specific PBPs targeted can influence the spectrum of activity and the likelihood of resistance development

Clinical Pearl: Understanding the mechanism of action helps explain why cephalosporins are ineffective against cell-wall deficient organisms like Mycoplasma or intracellular pathogens like Chlamydia.

Pharmacokinetics in Pediatrics

Understanding the pharmacokinetics of cephalosporins is crucial for optimal dosing in pediatric patients. Key aspects include:

1. Absorption

• Oral cephalosporins:
  • Variable bioavailability (20-90%)
  • Example: Cefpodoxime (50% bioavailability) vs. Cephalexin (90% bioavailability)
  • Food can delay absorption but generally doesn't affect total bioavailability
• Parenteral cephalosporins:
  • Complete bioavailability when given IV
  • IM administration also provides good bioavailability

2. Distribution

• Generally good distribution to most tissues and body fluids
• CSF penetration varies:
  • 3rd and 4th generation cephalosporins have excellent CSF penetration
  • 1st and 2nd generation have poor CSF penetration
• Volume of distribution (Vd) in infants and young children is larger than in adults
• Protein binding varies (e.g., Ceftriaxone: 85-95%, Cefazolin: 80%, Cefepime: 20%)

3. Metabolism

• Most cephalosporins undergo minimal hepatic metabolism
• Exceptions include Cefotaxime, which is partially metabolized to the active metabolite desacetylcefotaxime

4. Elimination

• Primarily renal excretion via glomerular filtration and tubular secretion
• Half-life is generally shorter in children compared to adults due to higher renal clearance
• Exceptions:
  • Ceftriaxone: Significant biliary excretion (40%)
  • Cefoperazone: Primarily biliary excretion

5. Age-Related Considerations

• Neonates:
  • Reduced renal function leads to prolonged half-lives
  • Lower protein binding can increase free drug concentrations
  • Immature blood-brain barrier increases CNS penetration
• Infants and young children:
  • Higher volume of distribution may necessitate weight-based dosing
  • Faster renal clearance may require more frequent dosing
• Adolescents:
  • Pharmacokinetics approach adult values
  • May require adult dosing based on weight

Clinical Pearl: The unique pharmacokinetics in pediatrics often necessitate more frequent dosing or higher mg/kg doses compared to adults to achieve similar drug exposures.

Indications and Clinical Use in Pediatrics

Cephalosporins are widely used in pediatric practice for various infections. The choice of specific agent depends on the suspected pathogen, site of infection, and local resistance patterns.

1. Respiratory Tract Infections

• Community-acquired pneumonia:
  • Ceftriaxone or Cefotaxime for hospitalized patients
  • Cefpodoxime or Cefuroxime for outpatient treatment
• Acute otitis media:
  • Cefdinir, Cefpodoxime, or Cefuroxime as second-line agents
• Sinusitis:
  • Cefdinir or Cefuroxime for patients with penicillin allergy

2. Central Nervous System Infections

• Bacterial meningitis:
  • Ceftriaxone or Cefotaxime as empiric therapy
  • Often combined with vancomycin for broader coverage
• Brain abscess:
  • Ceftriaxone in combination with metronidazole

3. Skin and Soft Tissue Infections

• Cellulitis:
  • Cephalexin for mild cases
  • Cefazolin for more severe cases requiring IV therapy
• Complicated skin infections:
  • Ceftaroline for MRSA coverage

4. Urinary Tract Infections

• Uncomplicated UTI:
  • Cephalexin or Cefixime as oral options
• Complicated UTI or pyelonephritis:
  • Ceftriaxone or Cefotaxime for initial IV therapy

5. Intra-abdominal Infections

• Appendicitis:
  • Ceftriaxone + Metronidazole for complicated cases
• Peritonitis:
  • Cefepime + Metronidazole for broader coverage

6. Bone and Joint Infections

• Osteomyelitis:
  • Cefazolin for methicillin-sensitive S. aureus
  • Ceftriaxone for gram-negative coverage
• Septic arthritis:
  • Cefazolin or Ceftriaxone depending on suspected pathogens

7. Prophylaxis

• Surgical prophylaxis:
  • Cefazolin for most clean and clean-contaminated procedures
• Prevention of recurrent UTIs:
  • Cephalexin as a prophylactic option in select cases

Clinical Pearls:

• Always consider local antibiotic resistance patterns when selecting a cephalosporin for empiric therapy.
• In areas with high prevalence of extended-spectrum beta-lactamase (ESBL) producing organisms, third-generation cephalosporins may not be appropriate for empiric treatment of gram-negative infections.
• Cephalosporins are not effective against atypical pathogens (e.g., Mycoplasma, Chlamydophila) or enterococci.
• When treating meningitis, choose cephalosporins with good CSF penetration (3rd or 4th generation).

Dosing and Administration in Pediatrics

Proper dosing of cephalosporins in pediatric patients is crucial for efficacy and safety. Dosing considerations include age, weight, renal function, and severity of infection.

General Dosing Principles:

• Doses are typically expressed in mg/kg/day
• Frequency of administration depends on the specific agent and clinical situation
• Renal dosing adjustments are often necessary for patients with impaired kidney function

Dosing Examples for Common Cephalosporins:

Drug	Indication	Dosing Regimen	Comments
Cephalexin	Mild to moderate infections	25-50 mg/kg/day in 2-4 divided doses	Max: 4g/day
Cefazolin	Surgical prophylaxis	30 mg/kg/dose (single dose)	Max: 2g
Cefuroxime	Respiratory tract infections	20-30 mg/kg/day in 2 divided doses (oral) 75-150 mg/kg/day in 3 divided doses (IV)	Max: 1g q8h (IV)
Ceftriaxone	Severe infections, meningitis	50-75 mg/kg/day in 1-2 doses 100 mg/kg/day for meningitis	Max: 2g q12h 4g/day for meningitis
Cefotaxime	Neonatal sepsis, meningitis	100-200 mg/kg/day in 3-4 divided doses	Max: 12g/day
Ceftazidime	Pseudomonal infections	100-150 mg/kg/day in 3 divided doses	Max: 6g/day
Cefepime	Severe nosocomial infections	100-150 mg/kg/day in 2-3 divided doses	Max: 2g q8h

Special Dosing Considerations:

1. Neonates:
   • Dosing intervals are often extended due to immature renal function
   • Example: Cefotaxime in neonates <7 days: 100 mg/kg/day in 2 divided doses
2. Renal Impairment:
   • Dose reduction or extended intervals may be necessary
   • Consult pediatric dosing references for specific adjustments
3. Obesity:
   • Consider using adjusted body weight for dosing in significantly obese children
4. Continuous Infusion:
   • Some cephalosporins (e.g., ceftazidime) may be administered as continuous infusions in critical care settings

Administration Guidelines:

• Oral administration:
  • Can be given with or without food (may improve GI tolerability)
  • Ensure proper reconstitution of suspensions
• IV administration:
  • Follow proper dilution and infusion rate guidelines
  • Avoid mixing with other medications in the same IV line
• IM administration:
  • Used less frequently in pediatrics due to pain
  • Ensure proper technique to avoid nerve injury

Clinical Pearls:

• For serious infections, use the higher end of the dosing range.
• Monitor renal function closely, especially with prolonged therapy or in critically ill patients.
• Consider therapeutic drug monitoring for certain cephalosporins (e.g., ceftazidime) in severe infections or altered pharmacokinetics.
• Be aware of the potential for biliary sludging with high-dose ceftriaxone, especially in neonates.

Adverse Effects and Management

While generally well-tolerated, cephalosporins can cause various adverse effects in pediatric patients. Understanding these effects and their management is crucial for safe use.

1. Gastrointestinal Effects

• Diarrhea: Most common adverse effect
  • Incidence: 5-25% depending on the agent
  • Management: Probiotics may help; consider C. difficile if severe
• Nausea and Vomiting:
  • More common with oral formulations
  • Management: Administer with food; consider antiemetics if severe
• C. difficile-associated diarrhea:
  • Risk increases with prolonged use
  • Management: Discontinue cephalosporin if possible; treat with oral vancomycin or fidaxomicin

2. Hypersensitivity Reactions

• Immediate reactions:
  • Incidence: 1-3%
  • Manifestations: Urticaria, angioedema, anaphylaxis
  • Management: Discontinue drug; treat anaphylaxis with epinephrine
• Delayed reactions:
  • Maculopapular rashes, fixed drug eruptions
  • Management: Antihistamines for symptomatic relief; discontinue if severe
• Cross-reactivity with penicillins:
  • Risk: ~2% for most cephalosporins, higher for first-generation
  • Approach: Cautious use in penicillin-allergic patients; consider skin testing

3. Hematologic Effects

• Eosinophilia: Usually transient and benign
• Neutropenia:
  • Risk increases with prolonged use (>10 days)
  • Management: Monitor CBC; discontinue if severe
• Thrombocytopenia: Rare, but reported with ceftriaxone
• Hemolytic anemia: Rare, associated with immune-mediated mechanisms

4. Renal Effects

• Nephrotoxicity:
  • Less common than with aminoglycosides
  • Risk factors: High doses, pre-existing renal impairment
  • Management: Monitor renal function; adjust dosing in renal impairment
• Interstitial nephritis: Rare, but can occur

5. Neurotoxicity

• Seizures:
  • Risk factors: High doses, renal impairment, CNS pathology
  • More common with cefepime
• Encephalopathy: Rare, but reported with cefepime

6. Other Effects

• Biliary sludging: With ceftriaxone, especially in neonates
• Drug fever: Can occur after several days of therapy
• Candidiasis: Oral or vaginal, due to alteration of normal flora

Clinical Pearls:

• Always assess risk-benefit ratio, especially for prolonged therapy.
• Educate parents about common side effects and when to seek medical attention.
• Consider probiotic supplementation for prevention of antibiotic-associated diarrhea.
• Monitor renal function and CBC in patients receiving prolonged courses.

Precautions and Contraindications

While cephalosporins are generally safe, certain precautions and contraindications should be considered in pediatric patients:

1. Allergic Reactions

• Penicillin Allergy:
  • Cross-reactivity risk: ~2% for most cephalosporins
  • Higher risk with 1st generation cephalosporins
  • Approach: Careful history taking; consider skin testing or graded challenge in uncertain cases
• Cephalosporin Allergy:
  • True IgE-mediated allergy is a contraindication
  • Consider alternative beta-lactams or non-beta-lactam antibiotics

2. Renal Impairment

• Dose adjustment often required
• Monitor renal function closely
• Consider alternative antibiotics in severe renal failure

3. Hepatic Impairment

• Generally safe, but use caution with ceftriaxone in severe liver disease
• Monitor liver function tests in prolonged therapy

4. Neonates

• Ceftriaxone:
  • Contraindicated in hyperbilirubinemic neonates
  • Risk of biliary sludging and kernicterus
• Cefotaxime: Preferred over ceftriaxone in neonates

5. Hematologic Disorders

• Use caution in patients with pre-existing cytopenias
• Monitor CBC in patients with hematologic disorders

6. Gastrointestinal Disorders

• Use with caution in patients with history of C. difficile infection
• Consider risk of pseudomembranous colitis in patients with IBD

7. Drug Interactions

• Probenecid: Increases cephalosporin levels
• Nephrotoxic drugs: Increased risk of renal toxicity
• Oral contraceptives: Potential decreased efficacy

8. Pregnancy and Lactation

• Generally considered safe in pregnancy (Category B)
• Most cephalosporins are compatible with breastfeeding
• Consider individual risk-benefit assessment

Clinical Pearls:

• Always obtain a thorough allergy history before prescribing cephalosporins.
• In penicillin-allergic patients, consider skin testing or graded challenge if cephalosporin use is essential.
• Be cautious with ceftriaxone in neonates, especially those with hyperbilirubinemia or receiving calcium-containing IV fluids.
• Adjust dosing in renal impairment to avoid toxicity while maintaining efficacy.

Resistance Mechanisms

Understanding resistance mechanisms is crucial for appropriate use of cephalosporins and prevention of further resistance development.

1. Beta-lactamase Production

• Extended-Spectrum Beta-Lactamases (ESBLs):
  • Hydrolyze 3rd and 4th generation cephalosporins
  • Common in Enterobacteriaceae (E. coli, Klebsiella)
  • Treatment: Carbapenems often required
• AmpC Beta-lactamases:
  • Inducible or constitutive
  • Confer resistance to 3rd generation cephalosporins
  • Common in Enterobacter, Citrobacter, Serratia
• Carbapenemases:
  • e.g., KPC, NDM-1
  • Hydrolyze almost all beta-lactams including carbapenems

2. Altered Penicillin-Binding Proteins (PBPs)

• MRSA: PBP2a with low affinity for beta-lactams
• Penicillin-resistant S. pneumoniae: Altered PBPs

3. Decreased Permeability

• Reduced expression of outer membrane porins
• Common in Pseudomonas aeruginosa, Acinetobacter

4. Efflux Pumps

• Active expulsion of antibiotics from bacterial cells
• Can confer multi-drug resistance

5. Target Site Modifications

• Rare for cephalosporins
• More common with other antibiotic classes

Strategies to Combat Resistance

• Appropriate use of cephalosporins based on local resistance patterns
• De-escalation of therapy when culture results are available
• Use of combination therapy in severe infections
• Implementation of antibiotic stewardship programs
• Regular surveillance of local resistance patterns

Clinical Pearls:

• Consider ESBL production in patients with recurrent UTIs or recent antibiotic exposure.
• Be aware of the potential for AmpC induction with 3rd generation cephalosporins in Enterobacter infections.
• In areas with high ESBL prevalence, consider carbapenems for empiric therapy of severe gram-negative infections.
• Utilize rapid diagnostic tests when available to guide appropriate antibiotic selection.

Comparison with Other Antibiotics

Understanding how cephalosporins compare to other antibiotic classes is essential for optimal antibiotic selection in pediatric practice.

1. Cephalosporins vs. Penicillins

Aspect	Cephalosporins	Penicillins
Spectrum	Broader, especially later generations	Narrower, focused on gram-positive
Beta-lactamase stability	Generally more stable	Less stable (except beta-lactamase inhibitor combinations)
CNS penetration	Excellent for 3rd/4th generations	Variable (good for high-dose penicillin G)
Allergy risk	Lower cross-reactivity risk	Higher allergy prevalence

2. Cephalosporins vs. Macrolides

• Spectrum: Cephalosporins lack coverage for atypical pathogens
• Mechanism: Cell wall inhibition vs. protein synthesis inhibition
• Resistance: Different resistance mechanisms
• Use in pneumonia: Often used in combination for comprehensive coverage

3. Cephalosporins vs. Fluoroquinolones

• Safety profile: Cephalosporins preferred in pediatrics due to better safety
• Spectrum: Fluoroquinolones have broader gram-negative and atypical coverage
• Resistance development: Higher concern with fluoroquinolones
• Route of administration: More oral options with fluoroquinolones

4. Cephalosporins vs. Aminoglycosides

• Toxicity: Cephalosporins have lower nephrotoxicity and ototoxicity risk
• Dosing: Cephalosporins allow for more flexible dosing schedules
• Spectrum: Aminoglycosides have better coverage for Pseudomonas
• Use in sepsis: Often used in combination for synergistic effect

5. Cephalosporins vs. Carbapenems

• Spectrum: Carbapenems have the broadest spectrum, including ESBL-producers
• Reserve status: Carbapenems are often considered last-line agents
• Anaerobic coverage: Most carbapenems have better anaerobic coverage
• Resistance concerns: Greater concern for promoting carbapenem resistance

6. Cephalosporins vs. Vancomycin

• MRSA coverage: Vancomycin effective; most cephalosporins lack MRSA activity
• Gram-negative coverage: Cephalosporins superior for gram-negatives
• Toxicity profile: Cephalosporins generally have a better safety profile
• Therapeutic drug monitoring: Required for vancomycin, not for cephalosporins

Situations Favoring Cephalosporins:

1. Empiric therapy for community-acquired infections
2. Meningitis (3rd/4th generation)
3. Surgical prophylaxis
4. Step-down therapy after broad-spectrum treatment
5. Penicillin-allergic patients (with caution)

Situations Favoring Other Antibiotics:

1. Known MRSA infections (vancomycin, linezolid)
2. Atypical pneumonia (macrolides)
3. ESBL-producing organisms (carbapenems)
4. Anaerobic infections (metronidazole, carbapenems)
5. Pseudomonas infections (anti-pseudomonal penicillins, carbapenems)

Clinical Pearls:

• Consider local resistance patterns when choosing between cephalosporins and other antibiotic classes.
• Use narrow-spectrum agents when possible to reduce selection pressure for resistance.
• Combine cephalosporins with other classes (e.g., macrolides in pneumonia) when atypical coverage is needed.
• Reserve carbapenems for serious infections with suspected ESBL-producers or in critically ill patients.
• In penicillin-allergic patients, cephalosporins may be a safe alternative, but assess the nature of the allergy first.

Future Perspectives

The development of new cephalosporins and cephalosporin combinations continues:

• Ceftolozane/tazobactam: Active against many MDR Pseudomonas strains
• Ceftazidime/avibactam: Active against KPC-producing organisms
• Cefiderocol: Novel siderophore cephalosporin with activity against carbapenem-resistant organisms

These newer agents may play important roles in treating multidrug-resistant infections in pediatric patients in the future, pending further studies and regulatory approvals for pediatric use.

First-Generation Cephalosporins: Overview

First-generation cephalosporins are characterized by their excellent activity against gram-positive organisms and moderate activity against gram-negative bacteria. They are widely used in pediatric practice for various infections.

Key Characteristics:

• Excellent activity against streptococci and methicillin-susceptible Staphylococcus aureus (MSSA)
• Moderate activity against some Enterobacteriaceae (E. coli, Klebsiella pneumoniae, Proteus mirabilis)
• No activity against enterococci, methicillin-resistant S. aureus (MRSA), or Pseudomonas aeruginosa
• Generally well-tolerated with a low incidence of side effects
• Available in both oral and parenteral formulations

Common Indications in Pediatrics:

• Skin and soft tissue infections
• Surgical prophylaxis
• Mild to moderate community-acquired pneumonia
• Uncomplicated urinary tract infections

Clinical Pearl: First-generation cephalosporins are excellent empiric choices for community-acquired skin and soft tissue infections in areas with low MRSA prevalence.

Cefazolin

Cefazolin is a parenteral first-generation cephalosporin widely used in pediatric practice.

Key Features:

• Route of Administration: Intravenous (IV), Intramuscular (IM)
• Spectrum of Activity: Excellent against gram-positive cocci, moderate gram-negative coverage
• Half-life: 1.5-2 hours (prolonged in neonates and renal impairment)
• Protein Binding: 80-85%
• CSF Penetration: Poor (not suitable for CNS infections)

Indications:

• Surgical prophylaxis (primary indication in pediatrics)
• Skin and soft tissue infections
• Bone and joint infections (MSSA)
• Pneumonia (non-severe community-acquired)

Dosing in Pediatrics:

• General dosing: 25-100 mg/kg/day divided every 8 hours
• Surgical prophylaxis: 25-50 mg/kg as a single dose (max 2g)
• Severe infections: Up to 100 mg/kg/day divided every 6-8 hours (max 6g/day)
• Neonates: Dosing interval adjusted based on gestational and postnatal age

Advantages:

• Excellent tissue penetration, making it ideal for surgical prophylaxis
• Low toxicity profile
• Cost-effective

Disadvantages:

• Requires parenteral administration
• Poor CNS penetration
• Not effective against MRSA or enterococci

Clinical Pearl: Cefazolin is the preferred agent for surgical prophylaxis in most pediatric procedures due to its excellent tissue penetration and favorable safety profile.

Cephalexin

Cephalexin is an oral first-generation cephalosporin commonly used in outpatient pediatric practice.

Key Features:

• Route of Administration: Oral
• Spectrum of Activity: Similar to cefazolin
• Half-life: 0.5-1.2 hours
• Protein Binding: 15%
• Bioavailability: 90%

Indications:

• Skin and soft tissue infections
• Streptococcal pharyngitis
• Uncomplicated urinary tract infections
• Mild community-acquired pneumonia

Dosing in Pediatrics:

• General dosing: 25-50 mg/kg/day divided every 6-8 hours
• Maximum dose: 4g/day
• For streptococcal pharyngitis: 20 mg/kg/dose twice daily for 10 days

Advantages:

• Excellent oral bioavailability
• Well-tolerated in pediatric patients
• Available as capsules and oral suspension

Disadvantages:

• Requires frequent dosing (usually four times daily)
• Taste of suspension may be unpalatable for some children
• Not effective against MRSA or resistant gram-negative organisms

Clinical Pearl: Cephalexin is an excellent choice for empiric treatment of uncomplicated skin and soft tissue infections in outpatient settings where MRSA prevalence is low.

Cefadroxil

Cefadroxil is an oral first-generation cephalosporin with the advantage of once or twice-daily dosing.

Key Features:

• Route of Administration: Oral
• Spectrum of Activity: Similar to other first-generation cephalosporins
• Half-life: 1.2-1.8 hours
• Protein Binding: 20%
• Bioavailability: 90%

Indications:

• Skin and soft tissue infections
• Pharyngitis
• Uncomplicated urinary tract infections

Dosing in Pediatrics:

• General dosing: 30 mg/kg/day divided every 12-24 hours
• Maximum dose: 2g/day

Advantages:

• Once or twice-daily dosing, improving compliance
• Good palatability of suspension
• Extended half-life compared to cephalexin

Disadvantages:

• Less extensively studied in pediatrics compared to cephalexin
• Not effective against MRSA or resistant gram-negative organisms

Clinical Pearl: Cefadroxil's once-daily dosing makes it an attractive option for improving adherence in treating uncomplicated infections in children.

Cephradine

Cephradine is a first-generation cephalosporin available in both oral and parenteral forms, though less commonly used in modern practice.

Key Features:

• Route of Administration: Oral, IV, IM
• Spectrum of Activity: Similar to other first-generation cephalosporins
• Half-life: 0.7-1 hour
• Protein Binding: 10-20%
• Bioavailability: 90% (oral)

Indications:

• Skin and soft tissue infections
• Respiratory tract infections
• Urinary tract infections

Dosing in Pediatrics:

• Oral dosing: 25-50 mg/kg/day divided every 6-12 hours
• IV/IM dosing: 50-100 mg/kg/day divided every 6 hours
• Maximum dose: 4g/day

Advantages:

• Available in both oral and parenteral forms
• Good oral bioavailability

Disadvantages:

• Less commonly used and studied in modern pediatric practice
• Short half-life necessitates frequent dosing
• Not effective against MRSA or resistant gram-negative organisms

Clinical Pearl: While effective, cephradine is less frequently used in current practice due to the availability of other first-generation cephalosporins with more convenient dosing schedules.

Cefapirine

Cefapirine is a parenteral first-generation cephalosporin with limited use in modern pediatric practice.

Key Features:

• Route of Administration: IV, IM
• Spectrum of Activity: Similar to other first-generation cephalosporins
• Half-life: 0.8-1.1 hours
• Protein Binding: 40-45%

Indications:

• Skin and soft tissue infections
• Respiratory tract infections
• Urinary tract infections

Dosing in Pediatrics:

• General dosing: 50-100 mg/kg/day divided every 6 hours
• Maximum dose: 4g/day

Advantages:

• Parenteral option for first-generation cephalosporin therapy

Disadvantages:

• Very limited use in current pediatric practice
• Less extensively studied compared to other first-generation cephalosporins
• Not effective against MRSA or resistant gram-negative organisms

Clinical Pearl: Cefapirine is rarely used in modern pediatric practice, with cefazolin being the preferred parenteral first-generation cephalosporin in most clinical scenarios.

Cefuroxime

Cefuroxime is a widely used second-generation cephalosporin in pediatric practice.

Formulations

• Oral: Cefuroxime axetil (prodrug)
• Parenteral: Cefuroxime sodium

Indications

• Upper and lower respiratory tract infections
• Otitis media
• Skin and soft tissue infections
• Urinary tract infections

Dosing

Oral: 10-15 mg/kg/dose twice daily (max 500 mg/dose)

IV/IM: 50-100 mg/kg/day divided every 8 hours (max 1.5 g/dose)

Advantages

• Good penetration into cerebrospinal fluid
• Effective against beta-lactamase producing H. influenzae and M. catarrhalis

Considerations

The oral suspension has a bitter taste, which may affect compliance in younger children.

Cefprozil

Cefprozil is an oral second-generation cephalosporin with extended gram-negative coverage.

Formulations

• Oral suspension
• Tablets

Indications

• Acute otitis media
• Pharyngitis/tonsillitis
• Uncomplicated skin and skin structure infections
• Acute sinusitis

Dosing

7.5-15 mg/kg/dose twice daily (max 500 mg/dose)

Advantages

• Better taste compared to cefuroxime axetil
• Twice-daily dosing improves compliance

Considerations

Not approved for use in infants under 6 months of age.

Cefaclor

Cefaclor is an oral second-generation cephalosporin with good activity against respiratory pathogens.

Formulations

• Oral suspension
• Capsules
• Extended-release tablets

Indications

• Otitis media
• Lower respiratory tract infections
• Pharyngitis
• Skin and skin structure infections
• Urinary tract infections

Dosing

Regular release: 20-40 mg/kg/day divided every 8 hours (max 1 g/day)

Extended-release: 375 mg twice daily for children ≥ 16 years

Advantages

• Good palatability of oral suspension
• Extended-release formulation available for older children

Considerations

Associated with a higher incidence of serum sickness-like reactions compared to other cephalosporins, particularly in young children.

Cefoxitin

Cefoxitin is a cephamycin antibiotic, often grouped with second-generation cephalosporins due to its similar spectrum of activity.

Formulations

• Parenteral: IV/IM injection

Indications

• Intra-abdominal infections
• Pelvic inflammatory disease
• Surgical prophylaxis
• Infections caused by anaerobic bacteria

Dosing

IV/IM: 80-160 mg/kg/day divided every 4-6 hours (max 12 g/day)

Advantages

• Excellent anaerobic coverage, including Bacteroides fragilis
• Resistant to many beta-lactamases

Considerations

Not effective against Pseudomonas aeruginosa. Limited oral bioavailability, so only available as a parenteral formulation.

Loracarbef

Loracarbef is a carbacephem antibiotic, structurally similar to second-generation cephalosporins and sharing a similar spectrum of activity.

Formulations

• Oral suspension
• Capsules

Indications

• Acute otitis media
• Acute maxillary sinusitis
• Pharyngitis and tonsillitis
• Acute bacterial exacerbations of chronic bronchitis
• Uncomplicated urinary tract infections

Dosing

15 mg/kg/day divided twice daily (max 400 mg/day)

Advantages

• Once or twice daily dosing improves compliance
• Good stability against beta-lactamases

Considerations

Not as widely used as other second-generation cephalosporins. Limited data on its use in children under 6 months of age.

Overview of Third-Generation Cephalosporins in Pediatrics

Third-generation cephalosporins are broad-spectrum antibiotics with enhanced activity against gram-negative organisms compared to earlier generations. They are widely used in pediatric practice due to their excellent efficacy, safety profile, and convenient dosing schedules.

General Characteristics:

• Broad-spectrum coverage, particularly against gram-negative bacteria
• Improved central nervous system penetration
• Greater stability against beta-lactamases
• Variable activity against Pseudomonas aeruginosa

Common Indications in Pediatrics:

• Meningitis
• Septicemia
• Complicated urinary tract infections
• Pneumonia
• Intra-abdominal infections
• Empiric therapy for febrile neutropenia

Ceftriaxone

Ceftriaxone is a widely used third-generation cephalosporin in pediatrics due to its long half-life allowing once-daily dosing.

Formulations:

• Parenteral: IV/IM injection

Indications:

• Meningitis
• Septicemia
• Community-acquired pneumonia
• Complicated urinary tract infections
• Acute otitis media
• Gonococcal infections

Dosing:

Standard dose: 50-75 mg/kg/day once daily or divided twice daily (max 2 g/day)

Meningitis: 100 mg/kg/day once daily or divided twice daily (max 4 g/day)

Advantages:

• Once-daily dosing in many indications
• Excellent CSF penetration
• Can be given IM when IV access is challenging

Considerations:

Can cause biliary sludging, especially with prolonged use. Not recommended in neonates due to its ability to displace bilirubin from albumin.

Cefotaxime

Cefotaxime is commonly used in neonates and young infants due to its safety profile and lack of biliary excretion.

Formulations:

• Parenteral: IV/IM injection

Indications:

• Neonatal sepsis
• Meningitis
• Pneumonia
• Intra-abdominal infections

Dosing:

Neonates: 50 mg/kg/dose every 8-12 hours

Infants and children: 150-200 mg/kg/day divided every 6-8 hours (max 12 g/day)

Advantages:

• Safe for use in neonates
• Good CSF penetration
• No biliary excretion

Considerations:

Requires more frequent dosing compared to ceftriaxone.

Ceftazidime

Ceftazidime is distinguished by its activity against Pseudomonas aeruginosa.

Formulations:

• Parenteral: IV/IM injection

Indications:

• Pseudomonal infections
• Febrile neutropenia
• Hospital-acquired pneumonia
• Complicated urinary tract infections

Dosing:

100-150 mg/kg/day divided every 8 hours (max 6 g/day)

Advantages:

• Excellent activity against Pseudomonas aeruginosa
• Good penetration into CSF

Considerations:

Less active against gram-positive organisms compared to ceftriaxone or cefotaxime.

Cefixime

Cefixime is an oral third-generation cephalosporin with extended gram-negative coverage.

Formulations:

• Oral suspension
• Tablets

Indications:

• Acute otitis media
• Pharyngitis
• Uncomplicated urinary tract infections
• Gonococcal infections

Dosing:

8 mg/kg/day once daily or divided twice daily (max 400 mg/day)

Advantages:

• Once-daily oral dosing
• Good activity against H. influenzae and M. catarrhalis

Considerations:

Limited activity against S. aureus. Not recommended for invasive or serious infections.

Cefpodoxime

Cefpodoxime is an oral third-generation cephalosporin with a broad spectrum of activity.

Formulations:

• Oral suspension
• Tablets

Indications:

• Acute otitis media
• Pharyngitis
• Community-acquired pneumonia
• Skin and soft tissue infections

Dosing:

10 mg/kg/day divided twice daily (max 400 mg/day)

Advantages:

• Broad spectrum of activity
• Twice-daily dosing

Considerations:

Should be administered with food to enhance absorption.

Ceftibuten

Ceftibuten is an oral third-generation cephalosporin with extended gram-negative activity.

Formulations:

• Oral suspension
• Capsules

Indications:

• Acute otitis media
• Pharyngitis
• Acute bronchitis

Dosing:

9 mg/kg/day once daily (max 400 mg/day)

Advantages:

• Once-daily dosing
• Good activity against respiratory pathogens

Considerations:

Limited activity against S. aureus. Not recommended for skin and soft tissue infections.

Overview of Fourth-Generation Cephalosporins in Pediatrics

Fourth-generation cephalosporins are advanced beta-lactam antibiotics that offer an expanded spectrum of activity compared to earlier generations. They are characterized by their enhanced stability against beta-lactamases and improved penetration through the outer membrane of gram-negative bacteria.

Key Characteristics:

• Broad-spectrum activity against both gram-positive and gram-negative bacteria
• Enhanced stability against many beta-lactamases
• Improved penetration into gram-negative bacteria
• Activity against Pseudomonas aeruginosa
• Good central nervous system penetration

Common Indications in Pediatrics:

• Febrile neutropenia
• Severe nosocomial infections
• Complicated intra-abdominal infections
• Severe pneumonia
• Meningitis (in some cases)

Advantages over Earlier Generations:

• Less susceptible to beta-lactamase-mediated resistance
• Broader spectrum of activity, especially against Pseudomonas and Enterobacteriaceae
• May be effective against some organisms resistant to third-generation cephalosporins

The most commonly used fourth-generation cephalosporin in pediatrics is cefepime. Cefpirome is another fourth-generation agent, but its availability and use vary by country.

Cefepime

Cefepime is the primary fourth-generation cephalosporin used in pediatric practice.

Formulations:

• Parenteral: IV/IM injection

Indications:

• Febrile neutropenia
• Severe nosocomial infections
• Complicated urinary tract infections
• Severe pneumonia
• Empiric therapy for suspected gram-negative infections in critically ill patients

Dosing:

Standard dose: 100-150 mg/kg/day divided every 8-12 hours (max 2 g/dose)

Severe infections/Pseudomonas: 150 mg/kg/day divided every 8 hours (max 2 g/dose)

Meningitis: 150 mg/kg/day divided every 8 hours (max 2 g/dose)

Advantages:

• Broad-spectrum activity including Pseudomonas aeruginosa
• Good penetration into cerebrospinal fluid
• Lower risk of inducing beta-lactamase production compared to third-generation cephalosporins

Considerations:

• Dose adjustment required in renal impairment
• May cause neurotoxicity, especially in patients with renal dysfunction or with excessive dosing
• Should be used judiciously to prevent development of resistance

Cefpirome

Cefpirome is another fourth-generation cephalosporin, though it's less commonly used than cefepime and not available in all countries.

Formulations:

• Parenteral: IV injection

Indications:

• Severe nosocomial infections
• Complicated urinary tract infections
• Severe community-acquired pneumonia
• Empiric therapy in febrile neutropenia

Dosing:

100 mg/kg/day divided every 12 hours (max 4 g/day)

Advantages:

• Broad-spectrum activity similar to cefepime
• Good tissue penetration
• Activity against some ceftazidime-resistant strains

Considerations:

• Less clinical experience in pediatrics compared to cefepime
• Not widely available in many countries
• Limited data on central nervous system penetration

Overview of Fifth-Generation Cephalosporins in Pediatrics

Fifth-generation cephalosporins represent the latest advancement in cephalosporin antibiotics. They are characterized by their expanded spectrum of activity, particularly against resistant gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA).

Key Characteristics:

• Activity against MRSA and other resistant gram-positive bacteria
• Maintained broad-spectrum activity against gram-negative organisms
• Enhanced binding to penicillin-binding proteins (PBPs)
• Stability against many beta-lactamases

Potential Indications in Pediatrics:

• Complicated skin and soft tissue infections
• Community-acquired pneumonia
• Infections caused by multidrug-resistant organisms

Considerations for Pediatric Use:

• Limited long-term safety data in children compared to older generations
• Use may be reserved for situations where older antibiotics are ineffective or contraindicated
• Ongoing clinical trials to establish safety and efficacy in various pediatric populations

The two main fifth-generation cephalosporins are ceftaroline and ceftobiprole, although their approval status and availability for pediatric use may vary by country.

Ceftaroline

Ceftaroline is the first fifth-generation cephalosporin approved for use in children in some countries.

Formulations:

• Parenteral: IV injection

Indications:

• Acute bacterial skin and skin structure infections (ABSSSI)
• Community-acquired bacterial pneumonia (CABP)

Dosing:

Children 2 months to < 2 years: 8 mg/kg every 8 hours

Children ≥ 2 years to < 18 years:

• < 33 kg: 12 mg/kg every 8 hours
• ≥ 33 kg: 400 mg every 8 hours or 600 mg every 12 hours

Maximum dose: 600 mg per dose

Advantages:

• Activity against MRSA and other resistant gram-positive organisms
• Maintained activity against common gram-negative pathogens
• Good safety profile in studied pediatric populations

Considerations:

• Limited data in neonates and infants under 2 months
• Dose adjustment required in renal impairment
• Not active against Pseudomonas aeruginosa or ESBL-producing organisms

Ceftobiprole

Ceftobiprole is another fifth-generation cephalosporin, but its approval and use in pediatrics are more limited compared to ceftaroline.

Formulations:

• Parenteral: IV injection

Potential Indications:

• Community-acquired pneumonia
• Hospital-acquired pneumonia (excluding ventilator-associated pneumonia)

Dosing:

Pediatric dosing is not yet well-established. Adult dosing is typically 500 mg every 8 hours.

Advantages:

• Broad-spectrum activity including MRSA and Pseudomonas aeruginosa
• Potential for use in mixed gram-positive and gram-negative infections

Considerations:

• Limited data on safety and efficacy in pediatric populations
• Not yet approved for use in children in many countries
• Ongoing clinical trials to establish pediatric dosing and indications