What are the best antibiotics for treating Multi-Drug Resistant (MDR) Klebsiella infections, particularly when using Ceftazidime (Cefta)-Avibactam and Aztreonam (AZTREONAM)?

Treatment of MDR Klebsiella with Ceftazidime-Avibactam and Aztreonam

For metallo-β-lactamase (MBL)-producing MDR Klebsiella, you must use ceftazidime-avibactam 2.5 g IV every 8 hours PLUS aztreonam 2 g IV every 6 hours as combination therapy; for KPC-producing or OXA-48-producing strains, use ceftazidime-avibactam monotherapy alone. 1, 2

Determine Carbapenemase Type First

The critical first step is identifying which carbapenemase your Klebsiella produces, as this determines whether you need combination therapy or monotherapy. 2

• Obtain phenotypic testing (modified carbapenem inactivation method with EDTA-CIM) or genotypic PCR testing for MBL genes (blaNDM, blaVIM, blaIMP) before initiating treatment whenever possible 1, 3
• If testing is unavailable or results are delayed, local epidemiology should guide empiric selection 1
• In China and many Asian regions, KPC predominates; in other regions, NDM-producing strains are increasingly common 1

Treatment Algorithm Based on Resistance Mechanism

For MBL-Producing Klebsiella (NDM, VIM, IMP)

Use ceftazidime-avibactam 2.5 g IV every 8 hours (as 2-hour infusion) PLUS aztreonam 2 g IV every 6 hours. 1, 2, 4, 5

• This combination demonstrates 30-day mortality of 19.2% versus 44% with alternative regimens including colistin-based therapies 1, 6, 7
• The Italian Society of Infection and Tropical Diseases provides a STRONG recommendation with MODERATE certainty of evidence for this combination over polymyxin-based regimens 1, 6, 7
• Synergistic activity occurs in 90% of MBL-producing strains because aztreonam is not hydrolyzed by metallo-β-lactamases, while avibactam protects aztreonam from co-produced ESBLs and cephalosporinases 1, 8, 9
• Clinical cure rates of 77.5% have been documented with this combination for NDM-producing infections 1
• The combination reduces aztreonam MICs by ≥4-fold and achieves ≥2.15-log10 CFU/ml bacterial reduction in time-kill assays 8, 3

For KPC-Producing or OXA-48-Producing Klebsiella

Use ceftazidime-avibactam 2.5 g IV every 8 hours as monotherapy (no aztreonam needed). 1, 2, 4

• Nearly 100% of KPC-producing and OXA-48-producing strains are susceptible to ceftazidime-avibactam 1, 2
• The Italian Society of Infection and Tropical Diseases provides a STRONG recommendation with MODERATE certainty of evidence for ceftazidime-avibactam or meropenem-vaborbactam in KPC-producing CRE 1
• Administer as prolonged 2-hour infusions (some data suggest 3-hour infusions improve 30-day survival) 2, 4
• Clinical success rates exceed those of polymyxin-based regimens with lower mortality 1

Dosing Specifications

Ceftazidime-Avibactam Dosing

• Standard dose: 2.5 g (ceftazidime 2 g + avibactam 0.5 g) IV every 8 hours 2, 4
• Infusion time: 2 hours (prolonged infusions optimize pharmacodynamics) 2, 4
• Renal adjustment required: Dose reduction necessary when CrCl <50 mL/min 4

Aztreonam Dosing (When Used for MBL-Producers)

• Standard dose: 2 g IV every 6 hours 6, 5
• Infusion time: Not specified in FDA labeling, but typically given over 20-60 minutes 5

Duration of Therapy

• Bloodstream infections: 7-14 days minimum 6, 4
• Pneumonia (HAP/VAP): 7-14 days 4
• Complicated intra-abdominal infections: 5-14 days (with metronidazole for anaerobic coverage) 4
• Bone/musculoskeletal infections: 4-6 weeks minimum 2, 6
• Continue therapy at least 48 hours after clinical improvement or bacterial eradication 6

Critical Pitfalls to Avoid

Never Use Aztreonam Monotherapy for MBL-Producers

Aztreonam alone will fail against MBL-producing Klebsiella because these organisms co-produce ESBLs and cephalosporinases that inactivate aztreonam. 6, 7, 5

Do Not Add Polymyxin or Fosfomycin Routinely

• The ceftazidime-avibactam plus aztreonam combination alone demonstrates superior outcomes compared to colistin-containing regimens 6, 7
• Adding additional agents increases toxicity without proven benefit 6

Monitor for Resistance Emergence

• Ceftazidime-avibactam resistance develops in 3.8-10.4% of patients during treatment of KPC-producing CRE 2, 6
• KPC variants (D179Y mutations in blaKPC-3) confer resistance to ceftazidime-avibactam 1
• Obtain repeat cultures if clinical deterioration occurs within 48-72 hours to assess for resistance development 2, 6

Wrong Carbapenemase Identification Leads to Treatment Failure

• Using ceftazidime-avibactam monotherapy for MBL-producers will fail because avibactam does not inhibit metallo-β-lactamases 1
• Conversely, adding aztreonam unnecessarily for KPC-producers increases cost and potential toxicity without benefit 2

Alternative Options When First-Line Therapy Unavailable

• Cefiderocol may be considered for MBL-producing Klebsiella with CONDITIONAL recommendation and LOW certainty of evidence (clinical cure 75% in CREDIBLE-CR trial subgroup) 1, 7
• Meropenem-vaborbactam is an alternative for KPC-producing strains, particularly for pneumonia due to superior lung penetration (ELF concentrations 63-65% of plasma) 1
• Imipenem-relebactam shows in vitro activity against KPC-producers but lacks robust clinical data 1

Monitoring Parameters

• Assess clinical improvement within 48-72 hours of therapy initiation 2, 6
• Monitor renal function closely as both ceftazidime-avibactam and aztreonam require dose adjustment in renal impairment 4, 5
• Obtain repeat cultures if fever persists beyond 72 hours or clinical deterioration occurs 2, 6
• No standardized antimicrobial susceptibility testing methods exist for the ceftazidime-avibactam plus aztreonam combination, so interpret MIC results cautiously 2