What is the role of Zavicefta (ceftazidime-avibactam) and aztreonam in the treatment of urosepsis?

Role of Zavicefta (Ceftazidime-Avibactam) and Aztreonam in Urosepsis Treatment

Ceftazidime-avibactam (Zavicefta) is recommended as a first-line treatment option for urosepsis caused by carbapenem-resistant Enterobacterales (CRE), while aztreonam should be reserved for cases with confirmed metallo-beta-lactamase (MBL) producing pathogens, potentially in combination with ceftazidime-avibactam. 1, 2

Ceftazidime-Avibactam in Urosepsis

Indications and Efficacy

• Ceftazidime-avibactam is recommended for complicated urinary tract infections (cUTIs) caused by carbapenem-resistant Enterobacterales at a dosage of 2.5 g IV q8h 1, 2
• It is particularly effective against Klebsiella pneumoniae carbapenemase (KPC)-producing organisms and OXA-48-producing Enterobacterales, which are common causes of urosepsis 2
• European Association of Urology guidelines recommend ceftazidime-avibactam as an appropriate treatment option for complicated UTIs, which can progress to urosepsis 1

Clinical Considerations

• For patients with urosepsis, early antimicrobial therapy must be initiated immediately after microbiological sampling to improve outcomes 1, 3
• Treatment success rates with ceftazidime-avibactam are comparable to best available therapy (91% vs 91%) for ceftazidime-resistant pathogens in complicated UTIs 4
• Resistance to ceftazidime-avibactam in KPC-producing organisms has been reported, particularly with prior ceftazidime-avibactam exposure, requiring careful monitoring 2

Aztreonam in Urosepsis

Indications and Efficacy

• Aztreonam is FDA-approved for urinary tract infections, including pyelonephritis and cystitis caused by susceptible Gram-negative microorganisms such as E. coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa 5
• Aztreonam is uniquely active against metallo-beta-lactamase (MBL)-producing CRE, which are resistant to ceftazidime-avibactam 1
• As monotherapy, aztreonam does not cover other broad-spectrum beta-lactamases or carbapenemases frequently co-produced by resistant strains 1

Dosing in Urosepsis

• For severe systemic infections like urosepsis, the recommended aztreonam dosage is 2 g every 6-8 hours 5
• Due to the serious nature of Pseudomonas aeruginosa infections, a dosage of 2 g every 6-8 hours is recommended at treatment initiation 5
• Dose adjustment is required in renal impairment, which is common in urosepsis patients 5, 6

Combination Approach for Complex Resistance Patterns

• For MBL-producing Enterobacterales causing urosepsis, the combination of ceftazidime-avibactam with aztreonam may be effective 7
• This combination leverages aztreonam's activity against MBL enzymes while avibactam protects aztreonam from other beta-lactamases 7
• In vitro studies show that ceftazidime does not negatively affect the activity of aztreonam/avibactam against MBL-producing Enterobacterales 7

Treatment Algorithm for Urosepsis

1. Initial Empiric Therapy:

   • Start with ceftazidime-avibactam 2.5 g IV q8h if CRE is suspected 1, 2
   • Consider local resistance patterns and patient risk factors for resistant organisms 3

2. After Culture Results:

   • For KPC or OXA-48 producing organisms: Continue ceftazidime-avibactam 2
   • For MBL-producing organisms: Add aztreonam 2 g IV q6-8h to ceftazidime-avibactam 1, 7
   • For susceptible organisms: De-escalate to narrower spectrum antibiotics based on susceptibility 1

3. Source Control:

   • Alleviate any urinary tract obstruction and drain significant abscesses 1
   • Replace or remove indwelling catheters before starting antimicrobial therapy 1

Important Caveats and Pitfalls

• Resistance development: Monitor for emergence of ceftazidime-avibactam resistance, especially with KPC-3 producers 2
• Renal function: Both drugs require dose adjustment in renal impairment; assess kidney function regularly 5, 6
• Combination therapy considerations: When using ceftazidime-avibactam plus aztreonam, remember that this is an off-label combination approach for MBL producers 7
• Duration of therapy: Generally 7-14 days depending on severity and response, with longer courses needed if prostatitis cannot be excluded in men 1