New Drugs for the Treatment of Pseudomonas aeruginosa Infections with Limited Treatment Options: A Narrative Review

Introduction

One of the most dangerous organisms that cause major hospital acquired infections is P. aeruginosa. It is naturally resistant to many antimicrobial treatments, and the management of such infections is further complicated by acquired resistance. Based on a review of the most recent microbiological and clinical studies, the most recent evidence and recommendations in favour of using ceftolozane-tazobactam and ceftazidime-avibactam, which have targeted clinical activity against a significant portion of P. aeruginosa strains with few treatment options, are described. Cefiderocol is also considered because of its strong in vitro performance against P. aeruginosa isolates, good stability to all-lactamases, and resistance to porin and efflux pump mutations. A overview of recently developed anti-pseudomonal antibiotics, including cefepime-taniborbactam and cefepime-zidebactam, is the focus of one part. Finally, various old antimicrobials that can be employed in combination methods, primarily fosfomycin, are outlined.

Ceftolozane-Tazobactam

Based on the studies conducted, ceftolozane-tazobactam represents a good option for the treatment of susceptible MDR/XDR P. aeruginosa infections, representing a first-line option in the CRPA as recently assessed by European guidelines, and also in the context of ICU severe infections and complex clinical scenarios such as real-life experiences assessed in studies. Caution should be advised in the determination of optimal dosing, e.g., in the presence of renal impairment, in appropriate dosing to achieve infusion appropriateness, and in possible combination therapy in selected settings such as high-inoculum infections where the emergence of resistance may be realized.

Ceftazidime-Avibactam

From reviewed data sourced from clinical real-life experiences, ceftazidime-avibactam emerges as a good option for the treatment of MDR/XDR P. aeruginosa infections, also in the case of strains harboring carbapenemases, and also in complex clinical conditions. Indeed, it is suggested as a targeted treatment in DTR P. aeruginosa infections with limited therapeutic options, thanks to high susceptibility rates in such cases. On the other hand, serious infections should be treated with caution in terms of cure and microbiological failure.

Cefiderocol

Cefiderocol, because of its strong activity and the high susceptibility of DTR P. aeruginosa strains, which is even higher than the newer BL-BLI combinations, Latest Drug Updates New Drugs for the Treatment of Pseudomonas aeruginosa Infections with Limited Treatment Options: A Narrative Review ICU NCA RITICAL CARE PDATES Latest Drug Update 2 shows considerable potential for the treatment of related infections. Very recent data found that cefiderocol, due to high microbiological eradication and clinical cure rates, could represent an important therapeutic option in DTR P. aeruginosa infections, in particular in the context of XDR and carbapenem-resistant strains, above all for MBL producers, and also in difficult clinical pictures. Testing the sensitivity of the compound is anyway suggested since resistant P. aeruginosa isolates have been described. Further data are needed to assess the impact of its use in combination.

Imipenem-Cilastatin-Relebactam

IDSA guidance on the treatment of P. aeruginosa with difficult-to-treat resistance suggests imipenem-cilastatin- relebactam therapy for cystitis, pyelonephritis, or cUTI and also for infections outside of the urinary tract. Instead, given the paucity of data on CRPA, ESCMID guidelines conclude on very low-certainty evidence for non-inferiority of imipenem-relebactam compared with colistin-meropenem combination therapy. Given the activity of imipenem-cilastatin-relebactam against ceftolozane-tazobactam-nonsusceptible isolates due to AmpC mutations, it could be considered a reasonable treatment option in these resistant strains. Data available about the efficacy of imipenem-cilastatin- relebactam are derived mainly from in vitro studies; therefore, future studies are needed to define its role in clinical practice, including the potential to develop resistance on treatment.

Meropenem-Vaborbactam

The activity of meropenem-vaborbactam against P. aeruginosa strains was found to be overall similar to that of meropenem alone. In a study conducted in the US, Lapuebla et al. showed that 79% of P. aeruginosa isolates were susceptible to meropenem, and the rate was not modified by adding vaborbactam. This is apparently because meropenem resistance in P. aeruginosa is primarily due to porin mutations or upregulation of efflux pumps, mechanisms that are not antagonized by vaborbactam. However, another study demonstrated that, with some P. aeruginosa strains, the addition of vaborbactam produced an increased bacterial killing in a neutropenic mouse thigh infection model, despite the in vitro MIC being the same for both agents, suggesting that these strains may contain an inducible β-lactamase that is inhibited by vaborbactam.

New β-Lactamase Inhibitor Combinations

Among cefepime-β-lactams inhibitor (BLI) combinations, which have demonstrated good in vitro activity against targeted GNB producing ESBLs, AmpC enzymes, and also carbapenemases such as cefepime-taniborbactam and cefepime-zidebactam, seem to potentiate cefepime activity against P. aeruginosa. Microbiological results suggest cefepime-taniborbactam as a potential future therapeutic option in patients infected with carbapenemase-producing Enterobacterales and CRPA isolates, including MBL producers. It is possible that an optimized drug exposure of cefepime at high doses as a prolonged infusion in combination with taniborbactam could cover most MBLs. Cefepime-zidebactam would be least impacted by diversity in local resistance mechanisms. Thus, it could become an interesting option for those contexts (i.e., Greece, Italy, and India) where the MBL and OXA-48-like carbapenemases are concerning.

Fosfomycin: Combination Strategy

Due to its in vitro bactericidal activity and selectivity of membrane channels, a combined strategy with fosfomycin for the treatment of DTR P. aeruginosa infections has arisen. The reported data confer on old fosfomycin a new role as an intravenous formulation, emerging as a well-tolerated antimicrobial option in combination in the complex setting of MDR/XDR P. aeruginosa infections.

Conclusions

The Public Health implications of P. aeruginosa with limited treatment options should not be ignored as it remains one of the major causes of healthcare-associated infection in Europe. Ceftolozane-tazobactam and ceftazidime-avibactam are safe, efficient, and carbapenem sparing options against DTR strains, but resistance against both compounds is already emerging, suggesting that, without a proper antimicrobial stewardship approach, these new drugs will lose their efficacy in a short time. Cefiderocol could represent an option when more complex mechanisms of resistance interact together as in XDR phenotypes and MBL-producer strains, and some of the new antimicrobial combinations in the pipeline seem promising as they could also be stable against most carbapenemases.

Imipenem-cilastatin- relebactam could be considered a reasonable treatment option against emerging ceftolozane-tazobactam- nonsusceptible isolates, but real-life studies to define its role are needed. The use of combination regimens should be assessed on an individual patient basis. Combination therapy with old drugs remains an option in case of deep-seated infections and in selected settings such as high-inoculum infections where the emergence of resistance is concerning and when MICs are high. Knowledge of specific resistance mechanisms gained through multiplex polymerase chain reaction (PCR) platforms is crucial for the stewardship of antimicrobial weapons.

Source:  Losito, A.R.; Raffaelli, F.; Del Giacomo, P.; Tumbarello, M. New Drugs for the Treatment of Pseudomonas aeruginosa Infections with Limited Treatment Options: A Narrative Review. Antibiotics 2022, 11, 579. https://doi.org/10.3390/antibiotics11050579.