Does Cefiderocol Have a Potential Role in Cystic Fibrosis Pulmonary Exacerbation Management?

Abstract

Cystic fibrosis (CF) is associated with frequent pulmonary exacerbations and the need for novel antibiotics against antimicrobial resistance. Cefiderocol is a newly approved therapeutic option active against a variety of multidrug resistant (MDR) bacteria such as gram-negative species commonly encountered by CF patients. This review describes the potential role of cefiderocol against Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Burkholderia cepacia complex. Cefiderocol is a potential therapeutic option for MDR pathogens with minimum inhibitory concentrations (MICs) of ≤4 mg/L. Due to the lack of in vivo evidence in the CF population, cefiderocol may be utilized in patients in which alternative options are lacking due to MDR organisms or rapid pulmonary decline.

Introduction

Cystic fibrosis (CF) is the most common autosomal recessive disease characterized by acute pulmonary exacerbations and airway infections. Pulmonary exacerbations have been associated with poor outcomes with many patients failing to return to their baseline lung function.^1–3 The release of pro-inflammatory cytokines, pulmonary injury, and impaired bacterial clearance leads to an increased number of bacteria and the potential for an exacerbation.⁴ Most pulmonary exacerbations are caused by bacterial infections from Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, and Burkholderia complex and from less common pathogens such as Achromobacter xylosoxidans, Stenotrophomonas maltophilia, and nontuberculosis Mycobacterium (NTM).⁵

These organisms have evolved to survive, due to a variety of intrinsic resistance mechanisms, increasing the prevalence of antimicrobial resistance and need for additional antibiotics.⁶ In this review, the authors aim to describe the potential role of cefiderocol for pulmonary exacerbations due to common bacterial organisms that are encountered by CF patients. The search strategy was completed in PubMed using search terms and Medical Subject Headings (MeSH) terms, including cefiderocol AND CF, cefiderocol AND P. aeruginosa, cefiderocol AND Burkholderia cepacia, cefiderocol AND S. maltophilia, and cefiderocol AND A. xylosoxidans. Two authors independently performed the primary article screening to select relevant articles for this review article.

Cefiderocol

Cefiderocol (Fetroja^®) is a siderophore cephalosporin that was recently approved by the U.S. Food and Drug Administration (FDA) in November 2019.⁷ The approval was supported by an international, multicenter, double-blind, randomized noninferiority trial that evaluated cefiderocol compared to imipenem/cilastatin (IPM/CS) in 452 patients hospitalized for complicated urinary tract infections (cUTI). Cefiderocol was well tolerated and superior for the primary end point of clinical cure and microbiologic eradication in 72% of patients compared to 55% within the IPM/CS group.⁸ It is active against a variety of multidrug resistant (MDR) gram-negative bacteria, including strains of Enterobacteriaceae, P. aeruginosa, and Acinetobacter baumannii. In addition, it is active against less common nonfermenters such as S. maltophilia, B. cepacia, Burkholderia pseudomallei, and Achromobacter species.^9,10

More specifically, in vitro studies have shown its activity against strains that produce carbapenemases, such as serine-carbapenemases (Klebsiella pneumoniae carbapenemase [KPC] and oxacillinase [OXA]) and metallo-β-lactamases (MBLs) such as New Delhi metallo, Verona integron-encoded MBL (VIM), and imipenemase MBL (IMP).^11–13 Siderophore antibiotics form a chelating complex with iron to utilize the bacterial iron transport system to penetrate into the outer membrane of susceptible microorganisms. This allows cefiderocol to overcome resistance from gram negative species by avoiding their porin channel mutations, overexpression of efflux pumps, and production of metallo carbapenemases. Cefiderocol can then bind to penicillin-binding proteins to inhibit peptidoglycan synthesis and therefore bacterial cell wall synthesis.¹⁴

Cefiderocol is administered as an intravenous (IV) 2 g dose given every 8 hours in patients with normal renal function, and there are adjustments needed for augmented renal clearance. Dose adjustments are also needed with moderate and severe renal impairment as cefiderocol is primarily excreted by the kidneys (∼90%) with minimal metabolism or hepatic involvement. There are currently no ongoing or published pharmacokinetic studies involving the use of cefiderocol within CF patients.

P. aeruginosa

Pseudomonas is a gram-negative bacterium belonging to the γ-proteobacteria with the most common type in humans being P. aeruginosa.¹⁵ It is often hospital-acquired and is the most common virulent respiratory pathogen in CF patients.¹⁶ The prevalence of P. aeruginosa infection increases with age, and 60–80% of adults with CF have chronic P. aeruginosa infections.¹⁷ P. aeruginosa infections are shown to increase the rate of lung function decline, progression to end-stage lung disease, and mortality compared to age-matched CF patients without P. aeruginosa.^18,19 This pathogen that has the ability to persist in the CF lung, and produce a biofilm, may undergo a phenotypic conversion to a mucoid form that can lead to antibiotic resistance.²⁰ In addition, clinical studies demonstrate the emerging resistance of P. aeruginosa from the intrinsic production of beta-lactamase (AmpC), outer membrane factor OprM, MBL, and overexpression of mexX and mexA (efflux pumps).^21–23

To overcome MDR P. aeruginosa, the standard treatment in CF patients involves the use of two different IV antipseudomonal antibiotics with synergistic mechanisms of action to reduce selection of resistant organisms.²⁴ Such combinations may include piperacillin/tazobactam, ceftolozane/tazobactam, ceftazidime/avibactam, cefepime, or a carbapenem plus a second antipseudomonal agent such as a fluoroquinolone, aminoglycoside, or colistin. Patients who have chronic colonization with P. aeruginosa are often placed on long-term azithromycin to impair biofilm formation through extensive quorum-sensing antagonistic activities.²⁵ In addition, inhaled antibiotics are often utilized to reduce the rate of pulmonary exacerbations from P. aeruginosa colonization.^24,26 Once established, chronic P. aeruginosa infections persist due to adaptive mechanisms and place patients at risk for frequent pulmonary exacerbations. Therefore, there is a need for novel treatment strategies to overcome resistance and improve clinical outcomes.

Cefiderocol has demonstrated in vitro efficacy against P. aeruginosa, including carbapenem-resistant isolates. Within P. aeruginosa carbapenem-resistant isolates (n = 182), cefiderocol (minimum inhibitory concentration [MIC] ≤0.03–4 mg/L) exhibited more potent in vitro activity than ceftolozane/tazobactam (MIC 2–64 mg/L) and ceftazidime/avibactam (0.25–64 mg/L).^27,28 Jacobs et al. evaluated the in vitro activity of cefiderocol and other antimicrobial agents (amikacin, ciprofloxacin, colistin, tigecycline, aztreonam, ceftolozane–tazobactam, cefepime, ceftazidime, ceftazidime–avibactam, and meropenem) against reference collections of carbapenem-resistant P. aeruginosa and found greater activity in cefiderocol with MICs ranging from ≤0.03 to 1 mg/L, with the MIC₉₀ being 0.5 mg/L. Data showed 100% susceptibility for 27 P. aeruginosa isolates, and resistance mechanisms included AmpC.²⁹

Additional studies demonstrated 485 P. aeruginosa carbapenem resistant isolates to be susceptible to cefiderocol with an MIC ranging from 0.002 to 8 mg/L.^30,31 Likewise, Dobias et al. demonstrated that cefiderocol was more active against 45 carbapenemase-producing P. aeruginosa isolates (MIC₉₀ 2–4 mg/L) than comparator agents (MIC₉₀ 4–>64 mg/L). Isolates were only susceptible to cefiderocol (MIC₅₀ = 0.5 mg/L, MIC₉₀ = 2 mg/L) and colistin (MIC₅₀ ≤0.5 mg/L, MIC₉₀ = 1 mg/L).³² However, due to the common utilization of aminoglycosides in CF patients, there is an increased incidence of nephrotoxicity when combined with colistin, and caution should be taken with this agent.^33,34 Cefiderocol was also found to be more efficacious than colistin in the in vitro study by Hsueh et al., where the MIC of cefiderocol was ≤1 mg/L (0.03, 0.06, 0.12, and 1 mg/L, respectively) for four colistin-resistant, imipenem-resistant P. aeruginosa isolates and a MIC = 4 mg/L of cefiderocol for one colistin-resistant, imipenem-resistant P. aeruginosa isolate.²⁷

In vivo studies have also demonstrated cefiderocol's sustained efficacy in reducing bacterial density of P. aeruginosa. Eight P. aeruginosa isolates were injected into neutropenic murine thigh models to investigate the efficacy of cefiderocol compared to cefepime and levofloxacin. The range of MICs (mg/L) for cefiderocol, cefepime, and levofloxacin was 0.063–0.5, 2–64, and 1–32, respectively, with additional pharmacokinetic studies revealing that the dosing regimen of cefiderocol was similar to the human regimen profile.

Cefiderocol produced efficacious activity, defined as ≥1 log₁₀ reduction in colony forming unit (CFU), against all the isolates and produced a ≥ 2 log₁₀ reduction in 7 of 8 isolates independent of fluoroquinolone and/or β-lactam susceptibility.^35,36 Matsumoto et al. evaluated the efficacy of cefiderocol against carbapenem-resistant P. aeruginosa in immunocompetent rat respiratory tract infection models. A total of 2 isolates, 1 MDR P. aeruginosa isolate and 1 cephalosporin-susceptible P. aeruginosa isolate, demonstrated cefiderocol MICs ranging from 0.125 to 8 μg/mL. The equivalent human exposure of 2 g every 8 hours as a 3-hour infusion for 4 days produced a > 3 log10 reduction in the number of viable cells in carbapenem-resistant isolates in the rat lungs.³⁷

Monogue et al. also demonstrated efficacy of cefiderocol against P. aeruginosa isolates, in neutropenic murine thigh models, with an MIC of 0.5 μg/mL, while these isolates were found to be resistant to meropenem and cefepime (MIC 8–128 μg/mL). At a MIC ≤4 μg/mL, cefiderocol caused bacterial stasis (≥1 log reduction) in 85% of P. aeruginosa isolates (n = 21). In addition, cefiderocol produced a mean bacterial reduction of 1.5 ± 0.4 log10 CFU at 24 hours in all cefepime and meropenem resistant isolates.³⁸ In the phase 2 trial, Portsmouth et al. evaluated cefiderocol compared to imipenem/cilastatin for the treatment of cUTI in 452 patients. Seven percent (n = 18) of patients in the cefiderocol group and 4.2% (n = 5) in the imipenem-cilastatin group were infected with P. aeruginosa as the primary uropathogen. The proportion of patients who met the outcome of test of cure was similar between the cefiderocol group (n = 7, 47%) and imipenem-cilastatin group (n = 2, 50%); however, this was much lower than the overall response rate in the cefiderocol group (73%) compared to the imipenem-cilastatin group (55%). The small sample size of P. aeruginosa isolates, as well as the possibility of biofilm formation within urinary catheters and stones, may explain why these patients had a lower microbiological response to P. aeruginosa.⁸

Most recently, the efficacy and safety of cefiderocol were investigated in a phase 3, randomized, open label international study (CREDIBLE-CR) in patients with carbapenem-resistant gram negative pathogens. Twenty-two patients (19%) were infected with P. aeruginosa with 45% of patients having nosocomial pneumonia. Clinical cure rates were similar in the cefiderocol group (50% [95% confidence interval (CI): 33.8–66.2]) compared to the best available therapy group (53% [28.90–75.60]) for nosocomial pneumonia. However, all-cause mortality differences were noted between the two groups with 25% for the cefiderocol group compared to 11% for the best available therapy group at day 14. This mortality difference was sustained until day 28 and was primarily seen in patients infected with Acinetobacter spp.

Cefiderocol drug adverse events that led to drug discontinuation included pyrexia, aminotransferase elevations, and a skin rash. Limitations of the CREDIBLE-CR study included a small sample size with a heterogeneous patient population and the use of only descriptive statistics for outcome data.³⁹ In contrast, APEKS-NP showed noninferior all-cause mortality between cefiderocol and extended infusion meropenem in patients with nosocomial pneumonia caused by gram negative microorganisms with the most common microorganisms being K. pneumoniae, P. aeruginosa, and A baumannii. Although there are no clinical trials for the use of cefiderocol in CF patients, this agent appears to be a potential therapeutic option for common MDR P. aeruginosa.⁴⁰

S. maltophilia

S. maltophilia is a gram-negative, aerobic, glucose nonfermenting motile bacillus. It is regarded as an organism of low virulence but is emerging as a multidrug resistant opportunistic pathogen, especially among immunocompromised hosts.⁴¹ S. maltophilia can be recovered from polymicrobial infections, most notably from the respiratory tract of CF patients, as a co-colonizer with P. aeruginosa.⁴² In 2019, the U.S Cystic Fibrosis Foundation annual data report found that the prevalence of S. maltophilia infections remained stable at 12% with a median age of 9 years old at first infection.¹⁶ According to SENTRY Antimicrobial Surveillance Program, trimethoprim/sulfamethoxazole (TMP/SMX) is the drug of choice for S. maltophilia with greater than 95% susceptibility worldwide.^43,44

Global resistance to S. maltophilia can be attributed to low membrane permeability, the presence of SME resistant efflux pumps, β-lactamases, and antibiotic-modifying enzymes such as aminoglycoside-modifying enzymes, AAC(6′). Specifically, S. maltophilia can acquire resistance to TMP/SMX through the sul1 gene, which is carried as a part of the class 1 integron, a group of resistant gene cassettes.^45,46 In vitro studies of S. maltophilia demonstrate susceptibility for other agents, including minocycline (95%), tigecycline (83.8%), moxifloxacin (80%), levofloxacin (76.3%), ticarcillin–clavulanate (76.3%), and ceftazidime (20%).^43,44

In a study conducted by Hackel et al., cefiderocol inhibited 100% (217/217) of the S. maltophilia isolates at a MIC of ≤4 mg/L.⁴⁷ Likewise, Rolston et al. evaluated 50 S. maltophilia isolates, and 100% were susceptible to cefiderocol at an MIC ≤4 mg/L and a MIC₉₀ of 0.25 mg/L.⁴⁸ Resistance rates to ceftazidime, levofloxacin, and TMP/SMX were 85%, 5%, and 5%, respectively, with three (15%) isolates intermediate to levofloxacin in 20 S. maltophilia isolates and all isolates susceptible to cefiderocol (MIC ≤2mg/L). Apart from cefiderocol, minocycline was the most active agent, with 100% of isolates being susceptible.^49–51 Similarly, 100 blood isolates of S. maltophilia revealed MICs of ≤1 mg/L for cefiderocol and superior susceptibility compared to ceftazidime, ceftazidime/avibactam, and ceftolozane/tazobactam.²⁷

Cefiderocol also showed superiority compared to aminoglycoside and carbapenem-resistant species with MICs ranging from ≤0.03 to 0.25 mg/L, with the MIC₉₀ being 0.25 mg/L.²⁹ In surveillance studies (SIDERO-WT), cefiderocol demonstrated potent activity against S. maltophilia isolates from North America and Europe with an MIC₉₀ range of 0.25–0.50 μg/mL. Cefiderocol inhibited 99.4–100% of all isolates at a MIC ≤4 mg/L. Contrastingly, the susceptibility of the S. maltophilia isolates to six comparator agents was inactive, with MIC₉₀ ≥64 μg/mL for cefepime, ceftazidime–avibactam, ceftolozane–tazobactam, and meropenem and >8 μg/ml for colistin and ciprofloxacin. This remarkable in vitro activity provides evidence that cefiderocol could be a potent therapeutic option against S. maltophilia infections and supports investigating in-depth in vivo studies.^47,52,53

A. xylosoxidans

A. xylosoxidans is an aerobic, motile, oxidase-positive, nonfermenting gram-negative bacillus.⁵⁴ A. xylosoxidans is primarily found in contaminated soil or water. Although it has low virulence, it is an opportunistic microbe and is known to infect patients such as those with CF.^55,56 A. xylosoxidans is found to infect 6% of CF patients and can develop into a persistent infection that accelerates the loss of lung function.¹⁶ A. xylosoxidans is usually susceptible to piperacillin–tazobactam, meropenem, trimethoprim–sulfamethoxazole, and ceftazidime and is frequently resistant to aminoglycosides, ampicillin, and first- and second-generation cephalosporins.^56–58 Resistance to these drugs are thought to have emerged due to B-lactamases and resistance-nodulation-division (RND) efflux pumps.^59–61

An in vitro study by Rolston et al. demonstrated that cefiderocol had a MIC of ≤4 μg/mL in 97% of A. xylosoxidans isolates with an MIC₉₀ of 0.125 μg/mL.⁴⁸ In addition, cefiderocol was utilized as salvage therapy in a case report of a 10-year-old female with ΔF508 and G542X mutations who had a rapid decline in her forced expiratory volume in one second (FEV1) over one year and an increase in hospital admissions due to pandrug resistant (PDR) Achromobacter spp. The patient received triple combination therapy with cefiderocol, meropenem/vaborbactam, and bacteriophage (Ax2CJ45φ2) during two separate admissions and had an increase in her FEV1 from 33% to 60% after 12 days of therapy. Subsequently, her FEV1 improved to 65% 8 weeks post-treatment. The authors reported that the Center for Disease Control and Prevention confirmed resistance to both cefiderocol and meropenem/vaborbactam with a cefiderocol MIC of 32 μg/mL. Although there was resistance, the use of all three agents, including a bacteriophage, led to a significant improvement in lung function, and there was no Achromobacter growth 16 weeks post treatment.⁶²

There are two additional case reports on compassionate use of cefiderocol in CF patients. The first was a CF male patient in his 20s who developed A. xylosoxidans bacteremia postlung transplant in addition to A. xylosoxidans pneumonia. He failed piperacillin–tazobactam monotherapy and improved with a combination regimen of cefiderocol and piperacillin–tazobactam and then 6 weeks later with cefiderocol and imipenem. The second case involved a female in her late teens with MDR A. xylosoxidans colonization who used cefiderocol as part of her planned peri-transplant regimen. She was treated with five weeks of meropenem and six weeks of cefiderocol post-transplant and was found to have asymptomatic A. xylosoxidans colonization at her four month follow-up. A. xylosoxidans was shown to be susceptible to cefiderocol in both cases (case #1 MIC = 0.12 mg/L; case #2 MIC = 1 mg/L).⁶³ These case reports suggest that cefiderocol may have promising results in patients colonized with MDR A. xylosoxidans who have frequent pulmonary exacerbations with rapid pulmonary decline with a lack of alternative options. Likewise, synergistic combinations may be utilized with cefiderocol and carbapenems for salvage therapy.

B. cepacia Complex

B. cepacia complex (BCC) is a group of 20 different aerobic, oxidase-positive, gram-negative bacteria species, including B. cepacia.^64,65 These bacteria are usually found in the soil, but are known to be infective pathogens in CF patients and are associated with chronic lung infections and progressive decline in lung function.^66,67 Currently, 3% of patients with CF are infected with BCC with a median age of 20 years old at the time of first infection.¹⁶ Current first line treatments for BCC include trimethoprim–sulfamethoxazole (TMP-SMX) and ceftazidime.⁶⁸ Doxycycline and minocycline are also options (46.4% and 45.9% of isolates susceptible, respectively), as well as ceftazidime–avibactam in some cases.^68,69 Mutations in the chromosomal RNA (B-lactamase resistance) and RND efflux pumps are thought to play a role in intrinsic and acquired multidrug resistance of BCC.^70,71

Several in vitro studies demonstrated positive results when using cefiderocol in B. cepacia. Karlowsky et al. found that at a MIC of ≤4 mg/L, 94.4% (84/89) of B. cepacia isolates were susceptible to cefiderocol. When tested against meropenem nonsusceptible isolates, cefiderocol had a MIC of ≤4 mg/L for 87.1% (27/31) of B. cepacia susceptible isolates.⁵² In the SIDER-WT-2014 study, 93.8% (11/12) of B. cepacia meropenem nonsusceptible isolates were susceptible to cefiderocol with an MIC ranging from 0.008 to 16 μg/mL. Only one isolate had an MIC of 16 μg/mL compared to 99.8% (11/12) isolates that had a cefiderocol MIC of ≤1 μg/mL.⁵³ B. cepacia demonstrated susceptibility to cefiderocol with in vitro studies revealing its potential benefit in CF patients with resistant B. cepacia.

Conclusion

P. aeruginosa, S. maltophilia, B. cepacia, and A. xylosoxidans are nonlactose–fermenting gram negative bacteria that are common opportunistic pathogens in the CF population. In vitro data demonstrate the potential use of cefiderocol as a potential therapeutic option for MDR pathogens with MICs of ≤4 mg/L. However, due to potential cost restraints and lack of clinical trials, cefiderocol should be reserved for patients in which alternative options are lacking due to MDR organisms or rapid pulmonary decline. Future research will help guide clinicians on the use of cefiderocol within the CF population, including postmarking safety concerns, lung pharmacokinetic penetration, and synergistic antibiotic combinations.

Footnotes

Disclosure Statement

No competing financial interests exist.

Funding Information

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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