Abstract
Background
This study evaluated the in vitro activity of cefiderocol, ceftazidime/avibactam, and aztreonam/avibactam against clinically important multidrug-resistant non-fermenting Gram-negative bacilli.
Methods
Bacteraemic isolates of 126 multidrug-resistant Acinetobacter baumannii (MDRAB), 110 imipenem-resistant Pseudamoas aeruginosa [including 14 difficult-to-treat resistant P. aeruginosa (DTRPA)], 45 beta-lactam-non-susceptible Burkholderia cepacia complex (BCC), 47 levofloxacin or trimethoprim/sulfamethoxazole-non-susceptible Stenotrophomonas maltophilia and 22 ciprofloxacin-non-susceptible Elizabethkingia spp. collected between 2019 and 2021 were subjected to MIC determination for cefiderocol, ceftazidime/avibactam and aztreonam/avibactam.
Results
The MIC50/90s of cefiderocol for drug-resistant A. baumannii, P. aeruginosa, BCC, S. maltophilia and Elizabethkingia spp. were 0.25/2, 0.25/1, ≤0.06/≤0.06, ≤0.06/0.25 and >32/>32 mg/L, respectively. Cefiderocol inhibited 94.4% (119/126) of MDRAB, 100% of imipenem-resistant P. aeruginosa, 100% of DTRPA and 100% of BCC at an MIC ≤4 mg/L, and 97.9% (46/47) of S. maltophilia at ≤1 mg/L. Ceftazidime/avibactam inhibited 76.4% (84/110) of imipenem-resistant P. aeruginosa, 21.4% (3/14) of DTRPA and 68.9% (31/45) of BCC at an MIC ≤8 mg/L. Aztreonam/avibactam had MIC50/90s of 16/>32, 8/16 and 4/8 mg/L for imipenem-resistant P. aeruginosa, BCC and S. maltophilia, respectively. At ≤8 mg/L, aztreonam/avibactam inhibited 7.1% (1/14) of DTRPA and 93.6% (44/47) of S. maltophilia isolates. Elizabethkingia spp. demonstrated high MICs for cefiderocol, ceftazidime/avibactam and aztreonam/avibactam, with all MIC50s and MIC90s > 32 mg/L.
Conclusion
Cefiderocol may serve as an alternative treatment for multidrug-resistant A. baumannii, P. aeruginosa, BCC and S. maltophilia when other antibiotics have been ineffective or intolerable. The role of ceftazidime/avibactam and aztreonam/avibactam in the management of BCC or S. maltophilia infections warrants further investigation.
Introduction
Non-fermenting Gram-negative bacilli (NFGNB) are important healthcare-associated pathogens that cause human diseases and can spread in hospital environments. Among NFGNB, Pseudamoas aeruginosa and Acinetobacter baumannii are the most common microorganisms causing nosocomial infections. Other less common bacteria, such as Stenotrophomonas maltophilia and Burkholderia spp., may also result in serious infection in vulnerable hosts.1
Treatment of NFGNB infections is challenging because they are intrinsically resistant to many antibiotics through beta-lactamase production, drug efflux or decreased permeability.2 Among these issues, beta-lactamase production is of special concern. In recent years, newer beta-lactam-beta-lactamase inhibitor combinations, such as ceftazidime/avibactam and aztreonam/avibactam, and a novel siderophore cephalosporin, cefiderocol, have been introduced to combat carbapenem-resistant GNB.3 The addition of avibactam overcomes the bacterial-resistance to ceftazidime and aztreonam.4 Cefiderocol binds to extracellular iron and is transported across the outer membrane through the iron transport system. These agents have shown a broad spectrum of activities against NFGNB.3 Recent data regarding the activities of cefiderocol and ceftazidime/avibactam have mainly focused on A. baumannii, S. maltophilia and/or P. aeruginosa.5,6 Data on the efficacy of these newer antimicrobial agents, including aztreonam/avibactam, against other NFGNB species are limited.
To address this unmet medical need, in the present study, we investigated the susceptibilities of clinical important multidrug-resistant NFGNB to cefiderocol, ceftazidime/avibactam and aztreonam/avibactam.
Methods
Non-duplicate blood isolates of multidrug-resistant NFGNB collected from patients at National Taiwan University Hospital during 2019–2021 were included and subjected to in vitro susceptibility testing. Five NFGNB spp. were selected: (i) multidrug-resistant A. baumannii (MDRAB), defined as A. baumannii that showed non-susceptibility to ≥1 agent in ≥3 antimicrobial categories,7 (ii) imipenem-resistant P. aeruginosa (IRPA), (iii) ceftazidime- and meropenem-non-susceptible B. cepacia complex (BCC), (iv) levofloxacin- or trimethoprim-sulfamethoxazole (TMP/SMX)-non-susceptible S. maltophilia and (v) ciprofloxacin non-susceptible Elizabethkingia spp. P. aeruginosa that is non-susceptible to piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem, ciprofloxacin and levofloxacin is defined as ‘difficult-to-treat’ resistant P. aeruginosa (DTRPA).8 Identification for resistance to traditional antibiotics was performed using the VITEK-2 system (bioMérieux, Inc., Hazelwood, MO, USA). Species identification was performed using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (Bruker Corporation, Billerica, MA, USA).
The MICs of cefiderocol, ceftazidime/avibactam and aztreonam/avibactam were determined using the broth microdilution method and interpreted according to CLSI guidelines.9 Cefiderocol and avibactam were provided by Shionogi & Co., Ltd (Osaka, Japan). Ceftazidime and aztreonam were obtained from the United States Pharmacopeia and Sigma-Aldrich (MO, USA), respectively. As aztreonam/avibactam does not have approved susceptibility breakpoints for P. aeruginosa, the CLSI susceptible breakpoint for aztreonam (MIC ≤8 mg/L) for P. aeruginosa was taken as the reference to interpret the results with a fixed concentration of avibactam at 4 mg/L. All IRPA isolates were assessed for carbapenemase production using the modified carbapenem inactivation method per CLSI method.9 Pulsed-field gel electrophoresis was performed on Elizabethkingia isolates as described protocol.10 Isolates with 80% similarity in banding patterns were considered identical pulsotypes.
Differences in susceptibility between antimicrobial agents were compared using the chi-squared test or Fisher’s exact test with Stata software (v.11; StataCorp, College Station, TX, USA). A two-tailed significance level of 0.05 was applied for all analyses.
Results
Between 2019 and 2021, 350 multidrug-resistant NFGNB isolates were collected, consisting of 126 MDRAB, 110 IRPA (including 14 DTRPA), 45 ceftazidime and meropenem-non-susceptible BCC, 47 levofloxacin or TMP/SMX-non-susceptible S. maltophilia and 22 ciprofloxacin-non-susceptible Elizabethkingia (21 E. meningoseptica and 1 E. miricola). The susceptibilities of these isolates to traditional antibiotics are shown in Table S1 (available as Supplementary data at JAC-AMR Online). None of the P. aeruginosa expressed a positive modified carbapenem inactivation method test result.
Table 1 presents the MIC results. Among MDRAB, cefiderocol exhibited an MIC range of ≤0.06 to >32 mg/L, with an MIC50 of 0.25 mg/L and an MIC90 of 2 mg/L. In addition, 94.4% of the MDRAB isolates were inhibited at ≤4 mg/L. Because ceftazidime/avibactam and aztreonam/avibactam are known to be inactive against carbapenem-resistant A. baumannii (CRAB),1,3 the MICs of these two agents were determined for only 30 randomly selected MDRAB isolates. Both ceftazidime/avibactam and aztreonam/avibactam displayed high MICs against tested MDRAB. The 110 IRPA were 100% susceptible to cefiderocol. Among them, 14 DTRPA and the remaining 96 IRPA isolates showed the same MIC50 (0.25 mg/L) and MIC90 (1 mg/L) values. Overall, 76.4% (84/110) of IRPA were inhibited at ceftazidime/avibactam MIC ≤8 mg/L. Compared with 14 DTRPA isolates, the remaining 96 non-DTRPA had lower MIC50 values for ceftazidime/avibactam (16 versus 8 mg/L) and aztreonam/avibactam (32 versus 16 mg/L), and higher susceptibility rates to ceftazidime/avibactam (21.4% versus 84.4%, P < 0.001) and aztreonam/avibactam (7.1% versus 43.8%, P = 0.013).
Table 1.
MICs of cefiderocol, ceftazidime/avibactam, and aztreonam/avibactam for five multidrug-resistant NFGNB
| Bacteria (no.) | Antibiotic | MIC (mg/L) | Percentage susceptible (breakpoint, mg/L) | ||
|---|---|---|---|---|---|
| MIC range | MIC50 | MIC90 | |||
| MDRAB (126) | CFD | ≤0.06 to >32 | 0.25 | 2 | 94.4 (≤4) |
| CZA | 32 to >32 | >32 | >32 | NA | |
| AZA | 16 to >32 | >32 | >32 | NA | |
| Imipenem-resistant PA (110) | CFD | ≤0.06–4 | 0.25 | 1 | 100 (≤4) |
| CZA | 0.5 to >32 | 8 | 32 | 76.4 (≤8/4) | |
| AZAa | 0.125 to >32 | 16 | >32 | 12.7 (≤8/4) | |
| Imipenem-resistant PA, excluding DTR strains (96) | CFD | ≤0.06–4 | 0.25 | 1 | 100 (≤4) |
| CZA | 0.5 to >32 | 8 | 16 | 84.4 (≤8/4) | |
| AZAa | 0.125 to >32 | 16 | >32 | 43.8 (≤8/4) | |
| DTRPA (14) | CFD | 0.125–4 | 0.25 | 1 | 100 (≤4) |
| CZA | 4 to >32 | 16 | >32 | 21.4 (≤8/4) | |
| AZAa | 4 to >32 | 32 | >32 | 7.1 (≤8/4) | |
| BCC, CAZ- and MEM-non-susceptible (45)b | CFD | ≤0.06–0.125 | ≤0.06 | ≤0.06 | 100 (≤4) |
| CZA | 2 to >32 | 8 | 32 | 68.9 (≤8/4) | |
| AZA | 8 to >32 | 8 | 16 | 86.7 (≤8/4) | |
| S. maltophilia, LEV or TMP/SMX-non-susceptible (47) | CFD | ≤0.06–2 | ≤0.06 | 0.25 | 97.9 (≤1) |
| CZA | 2 to >32 | >32 | >32 | NA | |
| AZA | 1–16 | 4 | 8 | NA | |
| Elizabethkingia species, CIP-non-susceptible (22) | CFD | 2 to >32 | >32 | >32 | NA |
| CZA | >32 to >32 | >32 | >32 | NA | |
| AZA | >32 to >32 | >32 | >32 | NA | |
AZA, aztreoman/avibactam; BCC, Burkholderia cepacia complex; CAZ, ceftazidime; CFD, cefiderocol; CIP, ciprofloxacin; CZA, ceftazidime/avibactam; DTR, difficult-to-treat resistance; LEV, levofloxacin; MDRAB, multidrug-resistant A. baumannii; MEM, meropenem; MIN, minocycline; NA, not applicable; PA, P. aeruginosa; TMP/SMX, trimethoprim-sulfamethoxazole.
aSusceptibility interpretations of AZA were based on CLSI aztreonam interpretive criteria against P. aeruginosa with a fixed concentration of avibactam at 4 mg/L.
bThe susceptibility interpretations of cefiderocol, CZA and AZA were based on same interpretive criteria against P. aeruginosa.
For BCC isolates, the cefiderocol MICs ranged from ≤0.06 to 0.125 mg/L, with both the MIC50 and MIC90 being ≤0.06 mg/L. Compared with cefiderocol, ceftazidime/avibactam and aztreonam/avibactam showed much higher MIC50/MIC90 values (8/32 mg/L and 8/16 mg/L, respectively) for these BCC isolates. Using the CLSI MIC breakpoints for P. aeruginosa as a reference, the susceptibility rates of BCC isolates to cefiderocol, ceftazidime/avibactam and aztreonam/avibactam would be 100%, 68.9% and 86.7%, respectively. Nine BCC isolates showed concurrent resistance to levofloxacin and TMP/SMX; all (9/9) of them had a cefiderocol MIC ≤4 mg/L.
Among S. maltophilia isolates that were non-susceptible to levofloxacin or TMP/SMX, 97.9% (46/47) were susceptible to cefiderocol. The cefiderocol MICs ranged from ≤0.06 to 2 mg/L, with an MIC50 ≤ 0.06 mg/L and an MIC90 of 0.25 mg/L. The MICs of ceftazidime/avibactam and aztreonam/avibactam for S. maltophilia ranged from 2 to >32 mg/L and from 1 to 16 mg/L, respectively. At ≤8 mg/L, aztreonam/avibactam inhibited 93.6% (44/47) of the S. maltophilia isolates. Elizabethkingia spp. demonstrated high MICs for cefiderocol, ceftazidime/avibactam and aztreonam/avibactam, with all MIC50 and MIC90 values >32 mg/L. Pulsed-field gel electrophoresis analysis of Elizabethkingia isolates revealed different pulsotypes with a dominant cluster of eight isolates (Figure S1). The distribution of the cefiderocol, ceftazidime/avibactam and aztreonam/avibactam MICs for five NFGNB spp. are shown in Figure 1, and Figures S2 and S3, respectively. Overall, drug-resistant BCC and S. maltophilia had lower MIC distributions of cefiderocol compared with drug-resistant P. aeruginosa and MDRAB.
Figure 1.
Distribution of cefiderocol MIC for five species of multidrug-resistant NFGNB. BCC, Burkholderia cepacia complex; CAZ, ceftazidime; CIP, ciprofloxacin; DTRPA, difficult-to-treat resistance P. aeruginosa; IRPA, imipenem-resistant P. aeruginosa; LEV, levofloxacin; MDRAB, multidrug-resistant A. baumannii; MEM, meropenem; NS, non-susceptible; TMP/SMX, trimethoprim-sulfamethoxazole; SM, S. maltophilia.
Discussion
This in vitro study demonstrated low cefiderocol MICs for MDRAB, DTRPA, drug-resistant BCC and S. maltophilia. Ceftazidime/avibactam inhibited 76.4% of IRPA and 68.9% of beta-lactam non-susceptible BCC at an MIC ≤8 mg/L. Aztreonam/avibactam had MIC50 values of 16, 8 and 4 mg/L for IRPA, drug-resistant BCC and S. maltophilia, respectively.
The high susceptibility rate for cefiderocol against MDRAB was consistent with previous investigations.5 However, the cefiderocol MICs were widely distributed, highlighting the importance of obtaining the MIC result of the target isolate when initiating cefiderocol therapy. Treatment-emergence resistance of cefiderocol has been reported in CRAB.11 In addition, cefiderocol for treatment of CRAB infections was associated with higher mortality than the best available therapy.12 These findings have raised concerns about the efficacy of cefiderocol monotherapy against CRAB, and experts suggest using cefiderocol in combination with other agents to treat CRAB infections.8
Among IRPA, DTRPA had lower susceptibility to ceftazidime/avibactam and aztreonam/avibactam than non-DTRPA, but all were 100% susceptible to cefiderocol. A previous study on MDR P. aeruginosa also reported a higher susceptibility rate to cefiderocol (97.3%) than to ceftazidime/avibactam (48.4%).13 Although cefiderocol was more potent against extensive-resistant P. aeruginosa than ceftazidime/avibactam, to our knowledge, there are no direct comparisons of clinical efficacy between these two agents for P. aeruginosa.
Earlier studies showed that cefiderocol inhibited 92.3%–95.5% of BCC isolates at an MIC ≤4 mg/L and 98.6%–100% of S. maltophilia isolates at ≤1 mg/L.6,14 However, reports on clinical use of cefiderocol in the treatment of BCC or S. maltophilia infections were still limited. Aztreonam/avibactam has been shown to inhibit 88.2%–97.9% of S. maltophilia at 8 mg/L,4,15 and treatment with aztreonam/avibactam successfully eradicated S. maltophilia bacteraemia in an immunocompromised patient.16 In the literature, 80% of Burkholderia strains are inhibited by ceftazidime/avibactam at an MIC ≤8 mg/L,17 and ceftazidime/avibactam as salvage therapy had cured an infant with persistent BCC bacteraemia.18 On the basis of limited data, ceftazidime/avibactam, aztreonam/avibactam, imipenem/relebactam, meropenem/vaborbactam and cefepime/zidebactam were ineffective against Elizabethkingia spp.19,20 Few studies investigating the cefiderocol MICs for Elizabethkingia showed low MICs (≤4 mg/L), but the resistance levels of tested Elizabethkingia isolates were either undescribed or ciprofloxacin-susceptible, which were different from our isolates.14,21
Our results support the recommendation of IDSA guidance to consider cefiderocol as an alternative or adjunctive treatment option for CRAB, DTRPA and S. maltophilia.8 However, as emphasized in the European guideline, clinical evidence of cefiderocol was still insufficient for these pathogens.22 This study has several limitations. First, this was a single-centre study and the sample size was modest for some NFGNB spp. Second, only bacteraemic isolates were included, and their susceptibility pattern may differ from isolates from other types of infection. Third, the initial selection of drug-resistant NFGNB isolates was based on susceptibilities reported by VITEK-2, which may not be consistent with results of broth microdilution methods. Nonetheless, in clinical practice, antimicrobial regimens have often been determined based on MIC results from the VITEK-2 system.
In conclusion, cefiderocol showed potent in vitro activity against multidrug-resistant A. baumannii, P. aeruginosa, BCC and S. maltophilia, which suggests its potential application as an alternative treatment when other antibiotics are ineffective or intolerable. More studies are needed to determine the activity of cefiderocol against drug-resistant Elizabethkingia spp.
Supplementary Material
Contributor Information
Yu-Shan Huang, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Yu-Chung Chuang, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Pao-Yu Chen, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Pei-Chun Chou, Laboratory of Infectious Disease, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Jann-Tay Wang, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Funding
The study was supported by the National Taiwan University Hospital, Taipei, Taiwan (grant number 112-N0075).
Transparency declarations
The authors have no conflict of interest.
Ethical approval statement
The study was approved by the NTUH Research Ethics Committee (registration number 202301184W).
Supplementary data
Figures S1 to S3 and Table S1 are available as Supplementary data at JAC-AMR Online.
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