What is the recommended treatment for OXA-48 (Oxacillinase-48) producing Klebsiella pneumoniae with meropenem?

Treatment of OXA-48-Producing Klebsiella pneumoniae: Meropenem Is NOT Recommended

Meropenem should NOT be used as monotherapy for OXA-48-producing K. pneumoniae infections; ceftazidime-avibactam is the first-line treatment of choice. 1, 2

Why Meropenem Fails Against OXA-48

• OXA-48 is a Class D serine carbapenemase that specifically hydrolyzes carbapenems including meropenem, rendering it ineffective despite in vitro susceptibility results that may appear favorable 2
• Even when OXA-48-producing isolates test as "meropenem-susceptible" (MIC ≤8 mg/L), clinical effectiveness is severely compromised and resistance emergence is highly probable during therapy 3
• A hollow-fiber infection model study demonstrated that meropenem shows low efficacy against OXA-48 producers even at high doses (2 grams every 8 hours), with strong bell-shaped relationships between dose and both antimicrobial effect and resistance emergence 3
• Critical pitfall: Do not rely on standard susceptibility testing alone—if OXA-48 is confirmed by molecular testing, meropenem is contraindicated regardless of reported MIC 2, 3

First-Line Treatment: Ceftazidime-Avibactam

• Ceftazidime-avibactam 2.5 grams IV every 8 hours is the first-line treatment for OXA-48-producing K. pneumoniae infections (CONDITIONAL recommendation, VERY LOW certainty of evidence) 1, 2
• Nearly 100% of OXA-48-producing CRE strains are susceptible to ceftazidime-avibactam because avibactam effectively inhibits this serine-based carbapenemase 2
• In a study of 57 CRE infections, ceftazidime-avibactam monotherapy achieved an 82.3% curative rate in 17 patients with OXA-48-positive infections 2
• Ceftazidime-avibactam monotherapy is appropriate for OXA-48 producers ONLY if there is no co-production of metallo-β-lactamases (NDM, VIM, IMP) 2

When to Add Aztreonam to Ceftazidime-Avibactam

• Add aztreonam 2 grams IV every 8 hours to ceftazidime-avibactam ONLY if the isolate co-produces both OXA-48 AND a metallo-β-lactamase (NDM, VIM, or IMP) 2, 4
• For NDM + OXA-48 co-producers, the combination therapy achieved a 77.5% curative rate 2
• The synergistic mechanism works by ceftazidime-avibactam neutralizing the OXA-48 enzyme while aztreonam remains stable against the metallo-β-lactamase 4
• Do not use ceftazidime-avibactam monotherapy if NDM or other MBL is co-produced—it will fail because avibactam has no activity against metallo-β-lactamases 2

What About Meropenem-Vaborbactam?

• Do not use meropenem-vaborbactam for OXA-48 infections—vaborbactam has no activity against OXA-48 carbapenemases 2, 4
• Meropenem-vaborbactam is effective for KPC-producing organisms but completely ineffective against OXA-48 producers 1

Limited Evidence for Meropenem-Based Combinations

• While some in vitro studies show synergy with double-carbapenem combinations (ertapenem + meropenem or imipenem + meropenem) against OXA-48 producers, synergy was observed in only 18.8% of isolate-combinations tested 5
• Fosfomycin combined with meropenem showed synergy in only 33% of OXA-48-producing strains in vitro 6
• There is insufficient clinical evidence to support meropenem-containing combination therapies for meropenem-resistant OXA-48 producers 7
• A retrospective cohort study of 117 OXA-48-producing K. pneumoniae infections found that combination therapy did not appear to confer additional benefit over monotherapy with active agents 8

Second-Line Options When Ceftazidime-Avibactam Is Unavailable

• Colistin remains a second-line option if in vitro susceptibility is demonstrated with an appropriate method, though it has significantly inferior outcomes and higher toxicity 7
• Cefiderocol may be considered as an alternative (CONDITIONAL recommendation, LOW certainty of evidence), though concerns exist regarding higher MIC values and treatment-emergent resistance 4, 7

Practical Algorithm for OXA-48 K. pneumoniae

1. Confirm carbapenemase type immediately using rapid molecular testing or epidemiological data 2
2. If OXA-48 alone: Start ceftazidime-avibactam 2.5g IV q8h monotherapy 2
3. If OXA-48 + MBL co-production: Start ceftazidime-avibactam 2.5g IV q8h PLUS aztreonam 2g IV q8h 2, 4
4. Do not delay treatment waiting for complete carbapenemase typing—initiate based on epidemiology or rapid testing 2
5. Ensure adequate source control including drainage of abscesses, removal of infected devices, and debridement of necrotic tissue 4

Dosing Adjustments

• Adjust ceftazidime-avibactam for renal function per package insert 2
• For meropenem (if used in rare circumstances with documented susceptibility and no alternatives): 500mg IV q8h for skin/soft tissue infections or 1g IV q8h for intra-abdominal infections, with renal dose adjustments per Cockcroft-Gault equation 9