Carbapenem Resistance - OXA48
A 39-year-old patient with an infected aortic endograft presents to the ER. He was hypotensive on admission, and the above organism was isolated in a blood culture. The salient phenotypic features of this organism are resistance to penicillins, cephalosporins, ceftolozane/tazobactam (breakpoint MIC ≤8), and carbapenem resistance (breakpoint MIC ≤1), but with MICs that are lower than a typical carbapenem-resistant organism. The mechanisms to consider with carbapenem resistance are KPC (Class A), OXA (Class D), a form of derepressed AmpC (Class C), or a combination of these.
The 3rd/4th generation cephalosporins are resistant, typically seen in KPC or OXA resistance mechanisms. A derepressed AmpC is less likely since a Class C Amp C-producing organism would be ceftolozane/tazobactam sensitive.
A Class B Metallo-beta lactamase (MBL) is less likely, considering that the aztreonam MIC is not lower. Since MBLs are resistant to traditional beta-lactamases, ceftolozane/tazobactam would be expected to show the resistance documented above.
Based on phenotypic interpretation, this organism is likelier to be a KPC or an OXA. Oxacillinases (OXA) do not hydrolyze carbapenems or penicillins, which may explain the lower MIC to imipenem and meropenem.
Since the meropenem and imipenem MICs = 4 (MIC sensitivity ≤1), OXA resistance is the most likely culprit. The 3rd/4th generation cephalosporins are also resistant, which can be less likely within OXA, although OXA organisms typically harbor numerous resistance mechanisms. This isolate is cefoxitin resistant, which could represent an AmpC beta-lactamase that is prevalent in Enterobacter isolates.
The most likely resistance mechanism is the OXA-type enzyme called OXA-48. This is the most common OXA enzyme within the Enterobacterales class.
This patient was empirically treated with cefiderocol. The cefiderocol MIC = 0.5. Cefiderocol was chosen because it can achieve a high serum concentration to clear bacteremia and is active against OXA-48 enzymes. A Verigene gram-negative panel later confirmed this blood isolate to be OXA-48.
OXA-48 carbapenemases are enzymes common within Enterobacterales and less common in Acinetobacter and Pseudomonas. OXA-48 is not as prevalent in the US as KPC, but it is significant due to the limited available treatment options. Identifying these organisms can be complex phenotypically, but here are some valuable tips.
OXA falls into the Class D ambler classification, making it different from other carbapenem resistance mechanisms (Class A ambler) we see within Enterobacterales. OXA enzymes preferentially hydrolyze penicillins more than carbapenems. Extended-spectrum cephalosporins are hydrolyzed to a much lower level.
With KPC resistance mechanisms, phenotypically, carbapenems have fully resistant MICs that are well above the resistant breakpoint MIC (meropenem/ imipenem MICs of ≥8 mcg/mL). This contrasts with OXA-48, where the level of carbapenem resistance is low. Colistin/polymyxin is more likely to be more active than meropenem/imipenem. It is important to note that a modified Hodge detects all carbapenemase production, and a Carba-NP test will typically be positive.
There are numerous newer antimicrobials on the market, including ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, cefiderocol, eravacycline, omadacyline, plazomicin, and imipenem/relebactam. Older antibiotics should also be considered in treating carbapenem-resistant organisms such as colistin, polymyxin, and tigecycline. Even though many of these are active against carbapenem-resistant strains like KPC, VIM, IMP, and NDM, the OXA enzymes function differently. In addition to colistin/polymyxin, only ceftazidime/avibactam, cefiderocol, plazomicin, and eravacycline are consistently active against organisms that produce OXA-48. Both plazomicin and eravacycline retain higher susceptibility to most OXA-48 isolates than the other options, but the serum concentration of these agents limits broad use. Eravacycline concentrates mainly in tissues, making it a less ideal option for bacteremia. Plazomicin concentrates in the urine and acts in a concentration-dependent fashion, limiting its utility in bacteremia. Although ceftazidime/avibactam and cefiderocol have cephalosporin backbones, their serum concentration is high, and the dosing is adequate for bacteremia with an increased inoculum.