What is the treatment for infections caused by bacteria positive for the OXA-48 gene?

What is OXA-48 and Treatment for OXA-48 Gene-Positive Infections

Understanding OXA-48

OXA-48 is a Class D carbapenemase enzyme that confers resistance to carbapenems and most β-lactam antibiotics, but remains susceptible to ceftazidime-avibactam. 1

• OXA-48 is an oxacillinase-type carbapenemase accounting for approximately 19% of carbapenem-resistant Enterobacterales (CRE) infections globally 1
• Unlike metallo-β-lactamases (MBLs), OXA-48 is a serine-based carbapenemase that can be inhibited by avibactam 2, 3
• OXA-48-producing organisms frequently co-harbor extended-spectrum β-lactamases (ESBLs) like CTX-M, creating complex resistance patterns 4

First-Line Treatment Recommendation

Ceftazidime-avibactam 2.5 grams IV every 8 hours (adjusted for renal function) is the first-line treatment for infections caused by OXA-48-producing Enterobacterales. 2, 3

• The International Journal of Antimicrobial Agents provides a CONDITIONAL recommendation with VERY LOW certainty of evidence for ceftazidime-avibactam as first-line therapy 2, 3
• Nearly 100% of OXA-48-producing CRE strains are susceptible to ceftazidime-avibactam 2
• Ceftazidime-avibactam monotherapy is appropriate for OXA-48 producers without co-production of metallo-β-lactamases 2

Clinical Evidence Supporting Treatment

• In a study of 57 CRE infections, the curative rate was 82.3% in 17 patients who received ceftazidime-avibactam alone for OXA-48-positive infections 2
• A retrospective cohort of 211 patients with OXA-48 infections treated with ceftazidime-avibactam showed 79% clinical cure and 21.6% 30-day mortality 5
• Real-world experience with 24 episodes of OXA-48 infections demonstrated 62.5% clinical cure at 30 days with 8.3% 30-day mortality and 20.8% 90-day mortality 6
• Ceftazidime-avibactam showed superior outcomes compared to older therapies, with better safety profiles than colistin-based regimens 6, 7

When to Add Aztreonam to the Regimen

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 curative rate was 77.5% with ceftazidime-avibactam plus aztreonam combination therapy 2
• Aztreonam is stable against metallo-β-lactamases because these enzymes cannot hydrolyze monobactam antibiotics 4
• The combination creates synergistic activity that restores full antimicrobial efficacy against dual carbapenemase producers 4

Critical Pitfalls to Avoid

• Do not use ceftazidime-avibactam monotherapy if NDM or other MBL is co-produced with OXA-48 - it will fail because avibactam has no activity against metallo-β-lactamases 4
• Do not use meropenem-vaborbactam for OXA-48 infections - vaborbactam has no activity against OXA-48 carbapenemases 4
• Do not delay treatment waiting for complete carbapenemase typing - initiate ceftazidime-avibactam immediately based on epidemiology or rapid molecular testing 2, 4
• Monitor for emergence of ceftazidime-avibactam resistance, which ranges from 0% to 12.8% in KPC-producing isolates and can occur through OXA-48 mutations (P68A, Y211S) 2, 8
• Avoid colistin-based regimens as first-line therapy due to significantly higher mortality compared to ceftazidime-avibactam 4

Dosing Considerations

• Standard dosing: ceftazidime-avibactam 2.5 grams (ceftazidime 2 grams + avibactam 0.5 grams) IV every 8 hours 2, 9
• Adjust both ceftazidime-avibactam and aztreonam (if used) for renal function 4
• Treatment duration typically ranges from 7-14 days depending on infection severity and source control 2, 9
• For combination therapy with aztreonam: 6/1.5 g of ceftazidime/avibactam and 8 g of aztreonam per day has been suggested based on PK/PD optimization 10

Combination Therapy Considerations

• Combination therapy with ceftazidime-avibactam had no direct impact on clinical outcomes for OXA-48 producers without MBL co-production 5
• Most patients (81%) received ceftazidime-avibactam as monotherapy with good outcomes for OXA-48 infections 7
• Empiric Gram-positive coverage with linezolid or vancomycin may be added while awaiting culture results, particularly in severe infections 9

Monitoring and Safety

• Adverse events related to ceftazidime-avibactam are uncommon, occurring in approximately 16.7% of patients, with renal impairment being the most frequent 6
• Recurrence rates at 90 days range from 10% to 35% depending on the study population 6, 7
• No emergence of ceftazidime-avibactam resistance was detected during treatment in multiple observational studies 7