Non-KPC Characteristics of Novel BL/BLI Compounds in Pseudomonas aeruginosa

Editor's Note: In the previous article, we provided a detailed overview of the advancements in the use of novel β-lactam/β-lactamase inhibitor (BL/BLI) combinations in Enterobacterales with various resistance mechanisms. This article continues the series by exploring the non-KPC characteristics of these novel BL/BLIs in treating Pseudomonas aeruginosa, specifically analyzing the potential value of ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/relebactam in combating multidrug-resistant Pseudomonas aeruginosa (MDR-PA) infections.

Resistance Mechanisms of Pseudomonas aeruginosa

Compared to Enterobacterales, the resistance mechanisms in Pseudomonas aeruginosa are more frequently regulated by alterations in membrane permeability through porin channels and efflux pump expression. The bacterium uses the OprD porin channel to uptake amino acids, allowing carbapenem entry into the cell while preventing the penetration of other β-lactams. Reduced OprD expression is associated with decreased sensitivity to carbapenems. Imipenem resistance primarily results from OprD downregulation, while the upregulation of efflux pump systems such as MexAB-OprM, MexCD-OprJ, and MexXY-OprM further diminishes sensitivity to meropenem. In addition to these permeability-mediated resistance mechanisms, Pseudomonas aeruginosa exhibits endogenous inducible resistance to β-lactams through chromosomal AmpC cephalosporinase (often referred to as Pseudomonas-derived cephalosporinases [PDCs]). Mutations in the AmpD gene and its homologs, which regulate AmpC production, can lead to the derepression of AmpC, increasing resistance to β-lactams. These resistance mechanisms, in combination with other potential β-lactamases (including but not limited to GES, VEB, PER, TEM, SHV, and OXA-10), make predicting susceptibility in Pseudomonas aeruginosa based on enzyme presence more challenging compared to Enterobacterales.

The Role of Different BLIs in MDR Pseudomonas aeruginosa

Both avibactam and relebactam have been shown to restore the activity of ceftazidime and imipenem, respectively, against MDR Pseudomonas aeruginosa (MDR-PA). One study found that, of 290 meropenem-nonsusceptible isolates collected from 34 hospitals, 157/290 (54%) were ceftazidime-nonsusceptible, and the addition of avibactam restored ceftazidime susceptibility in 105/157 (67%) of these isolates. An early study on relebactam found that adding it to imipenem reduced the minimum inhibitory concentrations (MICs) for all non-metallo-β-lactamase (MBL) Pseudomonas aeruginosa strains tested, including isolates with reduced OprD expression but no additional resistance mechanisms. The study noted that OprD-mediated imipenem resistance depends on AmpC activity, explaining why relebactam enhances imipenem activity in OprD-deficient isolates by inhibiting AmpC.

While vaborbactam effectively inhibits AmpC enzymes, meropenem monotherapy is stable against most PDCs, and Pseudomonas aeruginosa’s resistance to meropenem primarily arises through OprD loss and the upregulation of efflux pumps such as MexA-MexB-OprM. Therefore, adding vaborbactam does not significantly improve meropenem’s MIC against Pseudomonas aeruginosa. Although vaborbactam has shown no synergistic effect, varying European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints could lead clinicians to encounter Pseudomonas aeruginosa isolates that are resistant to meropenem (MIC >2 mg/L) but susceptible to meropenem/vaborbactam (≤8 mg/L). Notably, the Clinical and Laboratory Standards Institute (CLSI) has not yet defined breakpoints for meropenem/vaborbactam in Pseudomonas aeruginosa, so laboratories using CLSI standards should not report susceptibility results. Overall, ceftazidime/avibactam and imipenem/relebactam exhibit superior activity against Pseudomonas aeruginosa compared to their respective β-lactam backbone monotherapies, making them suitable for treating ceftazidime- and imipenem-resistant Pseudomonas aeruginosa infections. However, meropenem/vaborbactam should only be considered in rare instances where KPC carbapenemase is present, which accounts for only 0.53% of carbapenem-resistant Pseudomonas aeruginosa (CRPA) isolates in the U.S.

The Challenge of GES Enzymes

In the treatment of MDR-PA infections, the evolving global issue of GES enzymes must also be considered. Initially classified as extended-spectrum β-lactamases (ESBLs), certain GES variants developed the ability to hydrolyze carbapenems through single or dual amino acid substitutions. While cefoperazone/sulbactam is commonly used to treat MDR-PA, isolates harboring GES enzymes frequently develop resistance. However, even when MDR-PA exhibits resistance to cefoperazone/sulbactam, it often remains susceptible to ceftazidime/avibactam, making this a potential indicator of GES enzyme production. Among 807 global CRPA isolates, 106 (16%) were nonsusceptible to cefoperazone/sulbactam and did not produce MBLs, with 45% of these isolates harboring GES enzymes. Results indicated that 89% of GES-producing isolates were susceptible to ceftazidime/avibactam. The in vitro activity of ceftazidime/avibactam against GES-producing Pseudomonas aeruginosa was further supported by in vivo efficacy in a neutropenic mouse thigh infection model. In this model, imipenem/relebactam at human exposure levels achieved a ≥2-log reduction in bacterial burden in 4/5 clinical GES-producing Pseudomonas aeruginosa isolates, despite in vitro phenotypic resistance to the imipenem combination. Adding relebactam restored imipenem’s in vivo activity. Further research is needed to establish the efficacy of these BL/BLIs in treating GES-producing MDR-PA infections, but ceftazidime/avibactam appears to be a promising treatment option when phenotypically sensitive, while imipenem/relebactam may retain efficacy in vivo even when in vitro resistance is observed.

Other Class A ESBLs

In addition to GES, Pseudomonas aeruginosa is known to harbor other class A ESBLs, such as VEB and PER enzymes. Both of these enzymes hydrolyze ceftazidime and cefoperazone, while imipenem remains relatively stable against their hydrolytic activity. Adding avibactam or relebactam to β-lactams typically reduces the MIC several-fold, whereas tazobactam does not inhibit these enzymes. However, the presence of additional resistance mechanisms (e.g., OprD loss) may prevent MIC reductions from reaching the susceptible range, even when relebactam or avibactam can lower MICs. In fact, a recent study found that only 10/97 (10.3%) VEB-producing Pseudomonas aeruginosa isolates were susceptible to imipenem/relebactam. Clinicians should also monitor the expanding class D β-lactamase OXA-10 family. Initially unable to hydrolyze ceftazidime, OXA-10 family variants have since emerged that confer resistance to ceftazidime (OXA-14) and more recently, to ceftazidime/avibactam (OXA-14, OXA-794, OXA-795, and OXA-824), as well as carbapenems (OXA-40, OXA-198, OXA-655, and OXA-656). Given the current limited availability of diagnostic methods to detect these enzymes in clinical settings, susceptibility testing of novel BL/BLIs remains critical.

Exploration of Combination Therapy Strategies

Novel BL/BLIs, when combined with aztreonam, can be used to treat MBL-producing Pseudomonas aeruginosa infections. However, due to the bacterium’s diverse non-enzymatic resistance mechanisms, the synergistic effect of such combinations remains unclear. Data on using novel BL/BLIs for MBL-producing Pseudomonas aeruginosa are scarce, but the few available results suggest this strategy warrants further exploration. One study analyzed five MBL-producing Pseudomonas aeruginosa isolates resistant to aztreonam, aztreonam/avibactam, and ceftazidime/avibactam, finding that aztreonam combined with ceftazidime/avibactam restored bactericidal activity in four of the isolates. Another study showed less optimistic results, with MIC reductions of up to two-fold upon adding ceftazidime/avibactam to aztreonam, but this was only effective in aztreonam-susceptible isolates. Beyond in vitro studies, clinical reports on using aztreonam combined with a novel BL/BLI to treat MBL-producing Pseudomonas aeruginosa infections are extremely limited. One case report described a pneumonia patient infected with an NDM-1 and high-level AmpC-producing CRPA strain. The patient was treated with aztreonam plus ceftazidime/avibactam, showing synergistic effects as the MIC for aztreonam was reduced from 12 mg/L to 2 mg/L using the overlay gradient strip method, and the patient achieved clinical cure after a six-week course of therapy. A systematic review found that only 6% of MBL-producing Pseudomonas aeruginosa isolates had aztreonam MICs ≤4 mg/L when combined with avibactam. The authors concluded that the combination of ceftazidime/avibactam and aztreonam appears to be a promising option for treating MBL-producing pathogens, although its efficacy may be superior in Enterobacterales compared to Pseudomonas aeruginosa.

Treatment of CRPA

The key to treating CRPA is not assuming cephalosporin resistance. Several studies have demonstrated that carbapenem-resistant Pseudomonas aeruginosa isolates can remain susceptible to cephalosporins. For example, one study found that more than half (58%) of carbapenem-resistant isolates were still susceptible to ceftazidime. Additionally, imipenem/relebactam showed the greatest activity against ceftazidime-nonsusceptible isolates, while ceftazidime/avibactam exhibited stronger activity against carbapenem-nonsusceptible isolates. The various resistance mechanisms in Pseudomonas aeruginosa and their interactions can explain this counterintuitive finding. In 29 isolates displaying a phenotype of carbapenem resistance and cephalosporin susceptibility, OprD porin downregulation and upregulation of mexA and mexX efflux pumps were observed, with no detection of carbapenemase, ESBLs, or AmpC production. This type of resistance, characterized by OprD loss and low-level cephalosporinase expression, can result in carbapenem ineffectiveness while maintaining cephalosporin efficacy.

The Development of Resistance

The development of resistance to novel BL/BLIs in the treatment of Pseudomonas aeruginosa infections is a complex area of study. In one study involving 19 cases of MDR-PA treated with imipenem/cilastatin/relebactam, 26% (5/19) of previously imipenem/relebactam-resistant isolates subsequently regained susceptibility. Notably, all five patients had previously experienced treatment failure with Pseudomonas aeruginosa. While OprD plays a central role in imipenem resistance, whole-genome sequencing of these isolates revealed structural and transcriptional changes in efflux pumps that can expel relebactam, potentially contributing to resistance development. Ceftazidime/avibactam has also been linked to resistance development in treating Pseudomonas aeruginosa, although this is speculated to be driven by AmpC mutations. The clinical takeaway is that if a patient has been treated with a specific novel BL/BLI for a Pseudomonas aeruginosa infection and subsequently develops a suspected new infection or relapse, AST should be repeated. For clinically unstable patients, clinicians may consider switching to a different BL/BLI or alternative agent (e.g., cefiderocol) for empirical therapy while awaiting AST results.

Conclusion

In the treatment of Pseudomonas aeruginosa infections, ceftazidime/avibactam and imipenem/relebactam have demonstrated superior efficacy compared to ceftazidime and imipenem monotherapies. However, meropenem/vaborbactam does not show significant advantages over meropenem monotherapy.

While these novel BL/BLIs lack activity against MBL-producing bacteria, studies have shown that aztreonam combined with ceftazidime/avibactam is effective against Enterobacterales and certain strains of Pseudomonas aeruginosa. Further research is needed to determine whether meropenem/vaborbactam or imipenem/relebactam can also be effectively combined with aztreonam as a viable treatment option.