What is the recommended treatment approach for infections caused by OXA-48 (Oxacillinase-48) and NDM (New Delhi Metallo-beta-lactamase) producing bacteria in India?

From the Guidelines

The recommended treatment approach for infections caused by OXA-48 and NDM-producing bacteria in India is ceftazidime/avibactam plus aztreonam, as it has shown in vitro synergy and improved 30-day mortality rates compared to other antibiotics active in vitro, including colistin, tigecycline, and fosfomycin 1.

Treatment Approach

The treatment of infections caused by OXA-48 and NDM-producing bacteria in India is challenging due to the high prevalence of these resistant organisms.

• The combination of ceftazidime/avibactam plus aztreonam is preferred for the treatment of metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) infections, with a strong recommendation and moderate certainty of evidence 1.
• Cefiderocol may also be considered as an alternative option, with a conditional recommendation and low certainty of evidence 1.

Rationale

The rationale behind this recommendation is based on the limited clinical data available on the treatment of infections due to OXA-48-producing CRE and MBL-producing CRE.

• Ceftazidime/avibactam has shown in vitro activity against OXA-48-producing CRE, but the clinical experience is limited to observational studies with small sample sizes 1.
• The combination of ceftazidime/avibactam plus aztreonam has displayed in vitro synergy and improved 30-day mortality rates compared to other antibiotics active in vitro, including colistin, tigecycline, and fosfomycin 1.

Considerations

When treating infections caused by OXA-48 and NDM-producing bacteria in India, it is essential to consider the following:

• Antimicrobial susceptibility testing is crucial before initiating therapy as resistance patterns vary.
• Treatment duration typically ranges from 7-14 days depending on infection site and severity.
• The development of efficient MBL inhibitors is ongoing, and cefiderocol appears to be a promising therapeutic option, but its use against MBLs should be considered with caution due to high MIC values, risk of treatment-emergent resistance, and the role of combination therapy 1.

From the FDA Drug Label

Among Gram-negative uropathogens from both arms of Trial 2, genotypic testing identified certain ESBL groups (e.g., TEM-1, SHV-12, CTX-M-15, CTX-M-27, KPC-2, KPC-3, OXA-48) and AmpC beta-lactamases expected to be inhibited by avibactam in isolates from 273/281 (97. 2%) patients in the mMITT population.

The recommended treatment approach for infections caused by OXA-48 (Oxacillinase-48) and NDM (New Delhi Metallo-beta-lactamase) producing bacteria in India is not directly stated in the provided drug label. However, avibactam is expected to inhibit certain ESBL groups, including OXA-48.

• The clinical and microbiological cure rates for patients with ESBL-producing organisms, including OXA-48, were similar to the overall results in the trial.
• Avibactam in combination with ceftazidime may be considered as a treatment option for infections caused by OXA-48 producing bacteria.
• However, the label does not provide specific information on the treatment of NDM-producing bacteria. 2

From the Research

Treatment Approaches for OXA-48 and NDM Producing Bacteria

The prevalence of OXA-48 and NDM producing bacteria is high in India, and treating infections caused by these bacteria can be challenging.

• The best available treatment option for OXA-48 producers is ceftazidime-avibactam, where available and when the price permits its use 3.
• Colistin remains as the second-line option if in vitro susceptibility is demonstrated with an appropriate method 3.
• For NDM producers, ceftazidime-avibactam and aztreonam combination or cefiderocol can be used, where available 3.
• Higher cefiderocol MICs against NDM producers is concerning, and aztreonam-avibactam provides hope for the treatment of NDM producers 3.

Combination Therapies

Combination therapies have shown promise in treating OXA-48 and NDM producing bacteria.

• Ceftazidime-avibactam plus colistin, tobramycin, or tigecycline were more effective against OXA-48-producing Enterobacterales strains 4.
• The combination of ceftazidime-avibactam and aztreonam (CZA-ATM) or cefiderocol as monotherapy are considered the treatment of choice for NDM and OXA-48-producing Klebsiella pneumoniae infections 5.
• A case report showed that a patient with NDM and OXA-48-producing Klebsiella pneumoniae infection was successfully treated with CZA-ATM and high-dose tigecycline 5.

Resistance and Evolutionary Trade-Offs

The development of resistance to ceftazidime-avibactam is a concern, and evolutionary trade-offs may limit the evolution of OXA-48-mediated resistance.

• Exposure to ceftazidime-avibactam can lead to changes in OXA-48, resulting in increased ability to hydrolyze ceftazidime and withstand the inhibitory effect of avibactam 6.
• The compromising effect of the amino acid substitutions in OXA-48 on other β-lactams and the effect of ceftazidime-avibactam exposure on the epidemic OXA-48 plasmid indicate that the evolution of ceftazidime-avibactam resistance comes with collateral effects 6.