Aztreonam

Usage

Aztreonam is a synthetic monobactam antibiotic primarily prescribed for infections caused by susceptible gram-negative bacteria. It is effective against a broad range of gram-negative aerobes, including Pseudomonas aeruginosa, Enterobacteriaceae species (such as Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Serratia marcescens), and Haemophilus influenzae. It is indicated for various infections, including urinary tract infections, lower respiratory tract infections, skin and soft tissue infections, septicemia, intra-abdominal infections, gynecological infections, and meningitis. Additionally, inhaled aztreonam is specifically indicated for the suppressive therapy of chronic Pseudomonas aeruginosa lung infections in patients with cystic fibrosis aged six years and older.

Its pharmacological classification is antibiotic (specifically, a monobactam).

Aztreonam’s mechanism of action involves inhibiting bacterial cell wall synthesis by binding to penicillin-binding protein 3 (PBP3) of gram-negative bacteria. This binding disrupts the cross-linking of peptidoglycans, a crucial component of the bacterial cell wall, ultimately leading to bacterial cell death. It is highly resistant to hydrolysis by many narrow-spectrum β-lactamases, granting it effectiveness against bacteria that produce these enzymes.

Alternate Names

Aztreonam is also known as aztreonam lysine (for inhalation). Popular brand names include Azactam and Cayston.

How It Works

Pharmacodynamics: Aztreonam exerts its bactericidal effect by disrupting the synthesis of the bacterial cell wall. It specifically targets PBP3, which is essential for the final step of peptidoglycan cross-linking in gram-negative bacteria. This leads to cell wall instability and eventual bacterial lysis.

Pharmacokinetics:

• Absorption: Aztreonam administered intravenously or intramuscularly is rapidly and completely absorbed. Inhaled administration results in low systemic absorption.
• Distribution: It is widely distributed throughout the body, including the cerebrospinal fluid, achieving therapeutic concentrations in various tissues and organs.
• Metabolism: Aztreonam is not extensively metabolized.
• Elimination: Primarily eliminated via renal excretion, with approximately 60-80% of the administered dose excreted unchanged in the urine within 24 hours. A small portion is eliminated through biliary excretion. The elimination half-life is around 1.5-2 hours in adults with normal renal function.

Mode of Action: Aztreonam’s mode of action involves selective binding to and inhibition of PBP3 in gram-negative bacteria. This interference with PBP3 activity leads to a deficiency in peptidoglycan synthesis and consequent cell wall instability, resulting in bacterial cell death.

Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Aztreonam’s primary mechanism is the inhibition of PBP3, a bacterial enzyme. There is no significant interaction with human receptors or neurotransmitters.

Elimination Pathways: Aztreonam is predominantly eliminated through renal excretion. A minor fraction undergoes biliary excretion.

Dosage

Standard Dosage

Adults:

• Intravenous/Intramuscular:
  • Moderately severe systemic infections: 1-2 g every 8-12 hours.
  • Severe systemic or life-threatening infections: 2 g every 6-8 hours.
  • Urinary tract infections: 0.5-1 g every 8-12 hours.
  • Uncomplicated gonorrhea/cystitis (IM): 1 g single dose.
• Inhalation (Cayston): 75 mg three times daily (at least 4 hours apart) for 28 days, followed by a 28-day drug-free period. This cycle can be repeated.

Maximum daily dose: 8 g.

Children (over one week old):

• Intravenous:
  • Mild to moderate infections: 30 mg/kg every 6-8 hours.
  • Severe infections (2 years and older): 50 mg/kg every 6-8 hours.
  • Pseudomonal infections: 50 mg/kg every 6-8 hours.
• Maximum daily dose: Not to exceed adult maximum (8 g).

Special Cases:

• Elderly Patients: Renal function should be assessed; dose adjustments may be necessary based on creatinine clearance.
• Patients with Renal Impairment: Dosage adjustments are crucial. For creatinine clearance 10-30 mL/min, halve the dose after an initial loading dose. For creatinine clearance <10 mL/min, give one-fourth of the usual dose at standard intervals, with a supplemental dose (one-eighth of initial dose) after each hemodialysis session.
• Patients with Hepatic Dysfunction: No specific dosage adjustments are typically required. Monitoring is recommended.
• Patients with Comorbid Conditions: Consider potential drug interactions and adjust other medications as needed.

Clinical Use Cases:

Dosages in clinical settings generally adhere to standard recommendations based on infection severity and organism susceptibility. Empiric therapy with concurrent coverage for gram-positive organisms may be initiated in seriously ill patients.

• Intubation/Surgical Procedures/Mechanical Ventilation/ICU Use: Dosing follows standard guidelines based on the infection being treated.
• Emergency Situations: Standard dosing for severe or life-threatening infections applies.

Dosage Adjustments: Dose modification is required based on creatinine clearance in patients with renal impairment.

Side Effects

Common Side Effects:

• Injection site reactions (pain, redness, swelling).
• Nausea, vomiting, diarrhea.
• Rash.
• Dizziness, headache.

Rare but Serious Side Effects:

• Anaphylaxis (severe allergic reaction).
• Toxic epidermal necrolysis.
• Clostridioides difficile infection.
• Seizures.
• Hepatic dysfunction.
• Stevens-Johnson syndrome.

Long-Term Effects: Chronic complications are uncommon with appropriate use. Potential for C. difficile infection and development of antibiotic resistance with prolonged use.

Adverse Drug Reactions (ADR):

• Anaphylaxis.
• Toxic epidermal necrolysis.
• Severe C. difficile infection.

Contraindications

• Known hypersensitivity to aztreonam.

Drug Interactions

• Cefoxitin/Imipenem: May induce beta-lactamase production in some gram-negative bacteria, leading to antagonism with aztreonam. Avoid concurrent use.
• Oral anticoagulants: May prolong prothrombin time. Monitor coagulation parameters.
• Aminoglycosides: Increased risk of nephrotoxicity. Monitor renal function.
• Probenecid: Increases aztreonam serum levels.
• Cholera and typhoid vaccines: Aztreonam may interfere with the efficacy of live bacterial vaccines.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: B (Animal studies have not demonstrated fetal harm, but adequate human studies are lacking). Aztreonam crosses the placenta. Use only if clearly needed.
• Breastfeeding: Aztreonam is excreted in breast milk at low concentrations (<1% of maternal serum levels). Consider the benefits of breastfeeding alongside the potential risks to the infant. The American Academy of Pediatrics considers aztreonam compatible with breastfeeding.

Drug Profile Summary

• Mechanism of Action: Inhibits bacterial cell wall synthesis by binding to PBP3 of gram-negative bacteria.
• Side Effects: Common: injection site reactions, nausea, vomiting, diarrhea, rash. Serious: anaphylaxis, toxic epidermal necrolysis, C. difficile infection, seizures.
• Contraindications: Hypersensitivity to aztreonam.
• Drug Interactions: Cefoxitin, imipenem, oral anticoagulants, aminoglycosides, probenecid, cholera vaccine, typhoid vaccine.
• Pregnancy & Breastfeeding: Pregnancy Category B; use with caution. Compatible with breastfeeding according to the American Academy of Pediatrics.
• Dosage: See detailed section above.
• Monitoring Parameters: Renal function, liver function tests (periodically), signs of hypersensitivity, clinical response to therapy, and signs of superinfection (e.g., C. difficile infection).

Popular Combinations

Combination therapy is not routinely recommended unless the infection is polymicrobial or there is a high risk of resistance. If used, combinations are tailored to the specific pathogen(s) based on susceptibility testing.

Precautions

• General Precautions: Careful inquiry about prior hypersensitivity reactions to beta-lactam antibiotics. Monitor for signs of anaphylaxis.
• Specific Populations: See dosage adjustments for elderly and patients with renal impairment.
• Pregnant Women: Use only if clearly needed.
• Breastfeeding Mothers: Monitor infant for any adverse effects.
• Children & Elderly: Age-appropriate dosing is essential.
• Lifestyle Considerations: No specific restrictions related to alcohol, smoking, or diet are typically necessary. Driving may be impaired if dizziness or other central nervous system side effects occur.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Aztreonam?

A: The dosage varies depending on the infection’s severity, the patient’s age and renal function, and the route of administration. Refer to the detailed dosage section above for specific guidelines.

Q2: What are the common side effects of Aztreonam?

A: Common side effects include injection site reactions, nausea, vomiting, diarrhea, and rash.

Q3: How does Aztreonam work?

A: Aztreonam inhibits bacterial cell wall synthesis by binding to penicillin-binding protein 3 (PBP3) in gram-negative bacteria.

Q4: Is Aztreonam safe for pregnant or breastfeeding women?

A: Aztreonam is Pregnancy Category B. It should be used during pregnancy only if clearly needed. It is considered compatible with breastfeeding according to the American Academy of Pediatrics.

Q5: Can Aztreonam be used in patients with renal impairment?

A: Yes, but dosage adjustments are essential based on creatinine clearance.

Q6: What are the contraindications for Aztreonam?

A: Known hypersensitivity to aztreonam is the primary contraindication.

Q7: What are the key drug interactions to be aware of with Aztreonam?

A: Significant interactions include those with cefoxitin, imipenem, oral anticoagulants, and aminoglycosides.

Q8: What is the difference between Azactam and Cayston?

A: Both are brand names for aztreonam, but Cayston is specifically formulated for inhalation and is used in cystic fibrosis patients. Azactam is for intravenous or intramuscular administration.

Q9: Can Aztreonam be used for gram-positive infections?

A: No, Aztreonam is primarily effective against gram-negative bacteria. It has limited activity against gram-positive organisms.

Q10: How long should Aztreonam treatment typically last?

A: Treatment duration varies depending on the infection and clinical response. It should generally continue for at least 48 hours after symptoms resolve or evidence of bacterial eradication is obtained.