What antibiotics to use in a patient with Klebsiella pneumonia who has already been treated with meropenem, ceftazidime, and avibactam?

Treatment of Klebsiella pneumoniae After Failure of Meropenem and Ceftazidime-Avibactam

The critical first step is to immediately perform rapid molecular testing to identify the specific carbapenemase type, as this determines your salvage therapy choice: for MBL-producing strains use ceftazidime-avibactam PLUS aztreonam; for KPC variants with ceftazidime-avibactam resistance use meropenem-vaborbactam; and for OXA-48-like producers consider cefiderocol. 1

Immediate Diagnostic Action Required

Before selecting any salvage antibiotic, you must identify which carbapenemase mechanism is present 1:

• Class A (KPC): 47.4% of carbapenem-resistant K. pneumoniae 1
• Class B (MBLs - NDM, VIM, IMP): 20.6% of isolates 1
• Class D (OXA-48-like): 19.0% of isolates 1

The failure of both meropenem and ceftazidime-avibactam strongly suggests either an MBL-producing strain (which is intrinsically resistant to both agents) or a KPC variant with acquired ceftazidime-avibactam resistance mutations 1.

Treatment Algorithm Based on Carbapenemase Type

For MBL-Producing Klebsiella pneumoniae (Most Likely Scenario)

First-line therapy: Ceftazidime-avibactam 2.5g IV every 8 hours PLUS aztreonam 2, 1

• This combination is strongly recommended for severe infections caused by MBL-producing strains 2
• The combination showed 30-day mortality of 19.2% versus 44% with other regimens in bloodstream infections 1
• Aztreonam remains active against MBLs but is hydrolyzed by ESBLs; avibactam protects aztreonam from ESBL degradation while aztreonam covers the MBL 1, 3

Alternative option: Cefiderocol 1

• Clinical cure rates of 75% in MBL-producing CRE infections 1
• Recent data shows 70.8% clinical cure rates and 12.5% 28-day mortality with cefiderocol against MBL-producers 1
• Can be used as monotherapy for MBL infections 1

Critical pitfall to avoid: Do NOT use colistin-containing regimens as they showed the highest mortality rates in MBL infections 1

For KPC-Producing Strains with Ceftazidime-Avibactam Resistance

First-line therapy: Meropenem-vaborbactam 4g IV every 8 hours (infused over 3 hours) 2, 1

• KPC variants (particularly D179Y mutations in blaKPC-3) that confer ceftazidime-avibactam resistance often remain susceptible to meropenem-vaborbactam 2, 1
• Meropenem-vaborbactam showed higher clinical cure rates and decreased mortality compared to best available therapy in the TANGO II trial 2
• Resistance to ceftazidime-avibactam ranges from 0-12.8% in KPC-producing isolates and can emerge during therapy 1

Alternative option: Cefiderocol 1

• Can be considered for KPC-producing strains resistant to ceftazidime-avibactam 1

For OXA-48-Like Producing Strains

First-line therapy: Cefiderocol 1

• Should be considered as the first-line option for OXA-48 producers 1
• Limited clinical data exists but ceftazidime-avibactam showed promising results in small observational studies 1

Site-Specific Treatment Modifications

For Pneumonia

Prefer meropenem-vaborbactam over other options 2, 1

• Superior lung penetration with epithelial lining fluid concentrations of 63% for meropenem and 65% for vaborbactam 2, 1
• ELF concentrations remain several-fold higher than MIC90 of KPC-producing K. pneumoniae 2

For Bloodstream Infections

Avoid tigecycline monotherapy 1

• Low serum concentrations and poor outcomes in bacteremia 1
• Time to active antibiotic therapy critically influences outcomes in critically ill patients 1

For Urinary Tract Infections (Non-severe)

Consider aminoglycosides (including plazomicin) 1

• Suggested over tigecycline for complicated UTIs caused by CRE 1

Combination Therapy Considerations for Salvage Situations

When only older agents remain active in vitro 2, 1:

• For severe infections with limited options, use combination therapy with more than one in vitro active drug 2
• Fosfomycin-containing combinations showed reduced mortality (RR 0.55) compared to other regimens in CRKP infections, though evidence quality is very low 1
• When treating severe infections with polymyxins, aminoglycosides, or fosfomycin, use two in vitro active drugs 2

Avoid carbapenem-based combination therapy unless meropenem MIC is ≤8 mg/L, where high-dose extended-infusion meropenem may be used as part of combination therapy 2, 1

Critical Monitoring Requirements

• Perform therapeutic drug monitoring (TDM) when using polymyxins, aminoglycosides, or carbapenems, especially in critically ill patients 1
• Never delay appropriate therapy while awaiting susceptibility results; empiric therapy should be based on local epidemiology and rapid molecular diagnostics 1
• Follow-up blood cultures to document clearance of bacteremia 4

Duration of Therapy

• For uncomplicated bacteremia: minimum 7-14 days of appropriate therapy 4
• For complicated bacteremia with metastatic foci: 14-21 days typically required 4
• In neutropenic patients: continue therapy at least until neutrophil recovery (ANC >500 cells/mm³) 4