Heteroresistance to cefiderocol in carbapenem-resistant Acinetobacter baumannii in the CREDIBLE-CR study was not linked to clinical outcomes: a post hoc analysis.

IMPORTANCE: The population analysis profiling (PAP) test is considered the "gold standard" method to detect heteroresistance. It exposes bacteria to increasing concentrations of antibiotics at high cell densities to detect any minority resistant subpopulations that might be missed by the low inoculums used for reference susceptibility tests. However, its clinical relevance has not been well established. In the CREDIBLE-CR study, a numerically increased all-cause mortality was observed in the cefiderocol arm relative to the best available therapy arm for patients with Acinetobacter spp. infections. Heteroresistance has independently been proposed by another research group as a potential explanation of the mortality difference. An analysis of the baseline carbapenem-resistant Acinetobacter calcoaceticus-baumannii complex isolates from patients treated with cefiderocol in the CREDIBLE-CR study showed the highest clinical cure rate and the lowest mortality for patients with PAP-heteroresistant isolates compared with PAP-susceptible or PAP-resistant isolates. These findings contradict the abovementioned hypothesis that heteroresistance contributed to the increased mortality.

In vitro and in vivo activity of cefiderocol against Achromobacter spp. and Burkholderia cepacia complex, including carbapenem-non-susceptible isolates.

Achromobacter spp. and Burkholderia cepacia complex (Bcc) are rare but diverse opportunistic pathogens associated with serious infections, which are often multidrug resistant. This study compared the in vitro antibacterial activity of the siderophore antibiotic cefiderocol against Achromobacter spp. and Bcc isolates with that of other approved antibacterial drugs, including ceftazidime-avibactam, ciprofloxacin, colistin, imipenem-relebactam, and meropenem-vaborbactam. Isolates were collected in the SIDERO multinational surveillance program. Among 334 Achromobacter spp. isolates [76.6% from respiratory tract infections (RTIs)], cefiderocol had minimum inhibitory concentration (MIC)50/90 of 0.06/0.5 µg/mL overall and 0.5/4 µg/mL against 52 (15.6%) carbapenem-non-susceptible (Carb-NS) isolates. Eleven (3.3%) Achromobacter spp. isolates overall and 6 (11.5%) Carb-NS isolates were not susceptible to cefiderocol. Among 425 Bcc isolates (73.4% from RTIs), cefiderocol had MIC50/90 of ≤0.03/0.5 µg/mL overall and ≤0.03/1 µg/mL against 184 (43.3%) Carb-NS isolates. Twenty-two (5.2%) Bcc isolates overall and 13 (7.1%) Carb-NS isolates were not susceptible to cefiderocol. Cumulative MIC distributions showed cefiderocol to be the most active of the agents tested in vitro against both Achromobacter spp. and Bcc. In a neutropenic murine lung infection model and a humanized pharmacokinetic immunocompetent rat lung infection model, cefiderocol showed significant bactericidal activity against two meropenem-resistant Achromobacter xylosoxidans strains compared with untreated controls (P < 0.05) and vehicle-treated controls (P < 0.05), respectively. Meropenem, piperacillin-tazobactam, ceftazidime, and ciprofloxacin comparators showed no significant activity in these models. The results suggest that cefiderocol could be a possible treatment option for RTIs caused by Achromobacter spp. and Bcc.

In vitro efficacy of humanized regimen of flomoxef against extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae.

This study compared the efficacy of flomoxef with other ß-lactam antibiotics against extended-spectrum ß-lactamases (ESBL)-producing bacteria of clinical relevance. First, the prevalence and ß-lactamase genotypes of ESBL-producing strains among Escherichia coli and Klebsiella pneumoniae isolates collected in Japan from 2004 to 2018 were investigated. High MIC90 values (>64 µg/mL) of ceftriaxone, cefepime, and ceftazidime and low MIC90 values (≤0.06-2 µg/mL) of flomoxef, cefmetazole, and meropenem against both species were observed. Second, a chemostat model was used to analyze the efficacy of humanized regimens of three oxacephem/cephamycin antibiotics (flomoxef, cefmetazole, cefoxitin) and two other antibiotics (meropenem and piperacillin/tazobactam) in suppressing the growth of five ESBL-producing E. coli and two K. pneumoniae strains. Flomoxef, piperacillin/tazobactam, and meropenem showed good bactericidal effects with >4 log10 CFU/mL reduction without bacterial regrowth at 24 h even when the MIC of test isolates was >MIC90. Cefmetazole and cefoxitin resulted in regrowth of test isolates with MIC ≥MIC90 at 24 h. Cefmetazole, cefoxitin, flomoxef, and meropenem showed increased MICs for regrown samples. A clear relationship between the proportion of time that the free drug concentration exceeded the MIC (%fT>MIC) and antibiotic efficacy was found for flomoxef, cefoxitin, and cefmetazole, and flomoxef had the highest %fT>MIC, whereas discrepancies between Clinical and Laboratory Standards Institute breakpoint and bactericidal activity were observed for cefmetazole. Flomoxef was effective in preventing the growth of all ESBL-producing strains, even those with an MIC eight times the MIC90. Thus, flomoxef may be a good alternative to meropenem in context of carbapenems sparing stewardship.

Prospective role of cefiderocol in the management of carbapenem-resistant Acinetobacter baumannii infections: Review of the evidence.

Carbapenem-resistant Acinetobacter baumannii (CRAB) has been classified by the World Health Organization as being in the critical category of pathogens requiring urgent new antibiotic treatment options. Cefiderocol, the first approved siderophore cephalosporin, was designed for the treatment of carbapenem-resistant Gram-negative pathogens, particularly the non-fermenting species A. baumannii and Pseudomonas aeruginosa. Cefiderocol is mostly stable against hydrolysis by serine ß-lactamases and metallo-ß-lactamases, which are leading causes of carbapenem resistance. This review collates the available evidence on the in vitro activity, pharmacokinetics/pharmacodynamics, and efficacy and safety of cefiderocol, and outlines its current role in the management of CRAB infections. In vitro surveillance data show susceptibility rates of >90% for cefiderocol against CRAB isolates as well as in vitro synergism with a variety of antibiotics recommended in guidelines. Clinical efficacy of cefiderocol monotherapy against CRAB infections has been demonstrated in the descriptive, open-label CREDIBLE-CR and the non-inferiority, double-blind APEKS-NP randomised clinical trials as well as in real-world cases in patients with underlying health problems. To date, the frequency of on-therapy development of cefiderocol resistance in A. baumannii appears to be low, but monitoring is highly recommended. Within current treatment guidelines for moderate-to-severe CRAB infections, cefiderocol is recommended for infections in which other antibiotics failed and in combination with other active antibiotics. In vivo pre-clinical data support the combination of sulbactam or avibactam with cefiderocol to enhance efficacy and to suppress the emergence of cefiderocol resistance. The benefit of combination therapy in the clinical setting is yet to be determined in prospective studies.

In vitro activity of cefiderocol against MBL-producing Gram-negative bacteria collected in North America and Europe in five consecutive annual multinational SIDERO-WT surveillance studies (2014-2019).

OBJECTIVES: To evaluate the in vitro antibacterial activity of cefiderocol, a siderophore cephalosporin against MBL-producing clinical isolates. METHODS: MBL-producing strains were selected from clinical isolates of Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii complex collected in North America and Europe in five consecutive annual multinational SIDERO-WT surveillance studies from 2014 to 2019. MICs of cefiderocol and comparator agents were determined by the broth microdilution method according to the CLSI guideline. RESULTS: A total of 452 MBL-producing strains consisting of 200 Enterobacterales, 227 P. aeruginosa and 25 A. baumannii complex were identified. The highest number of MBL-producing Enterobacterales strains were detected in Greece. MBL-producing strains of both P. aeruginosa and A. baumannii complex were isolated most frequently in Russia. For Enterobacterales, 91.5% or 67.5% of MBL-producing strains had cefiderocol MIC values ≤4 mg/L (CLSI susceptibility breakpoint) or ≤2 mg/L (EUCAST susceptibility breakpoint), respectively. All MIC values of cefiderocol for MBL-producing P. aeruginosa strains were ≤4 mg/L (CLSI susceptibility breakpoint), and 97.4% of them had cefiderocol MIC values ≤2 mg/L (EUCAST susceptibility breakpoint). For A. baumannii complex, 60.0% or 44.0% of MBL-producing strains had cefiderocol MIC values ≤4 mg/L (CLSI susceptibility breakpoint) or ≤2 mg/L (EUCAST pharmacokinetic-pharmacodynamic susceptibility breakpoint), respectively. Against all types of MBL-producing strains, MIC distribution curves of cefiderocol were located in the lowest numerical values, compared with other ß-lactams and ß-lactam/ß-lactamase inhibitor combinations tested and ciprofloxacin. CONCLUSIONS: Although the types of MBL-producing strains isolated by country varied, cefiderocol showed potent in vitro activity against all types of MBL-producing Gram-negative bacteria regardless of the bacterial species.

Cefiderocol Treatment for Patients with Multidrug- and Carbapenem-Resistant Pseudomonas aeruginosa Infections in the Compassionate Use Program.

Cefiderocol is an option for infections caused by multidrug-resistant Pseudomonas aeruginosa, but its in vitro activity against these isolates and its clinical effectiveness for isolates with MICs of >1 µg/mL is unclear. We investigated the in vitro activity of cefiderocol against P. aeruginosa isolates collected from patients treated with cefiderocol through the compassionate use program and assessed physician-reported clinical response and 28-day all-cause mortality by cefiderocol MIC values. P. aeruginosa isolates underwent susceptibility testing to cefiderocol and comparator agents by using reference broth microdilution. U.S. Food and Drug Administration (FDA; susceptible, ≤1 µg/mL) and Clinical and Laboratory Standards Institute (CLSI; susceptible, ≤4 µg/mL) cefiderocol breakpoints were applied. Additionally, molecular characterization of ß-lactamase genes was performed. Clinical response and vital status were reported by treating physicians. Forty-six patients with P. aeruginosa infections were evaluated. Twenty-nine (63%) and 42 (91%) isolates were susceptible to cefiderocol using FDA and CLSI breakpoints, respectively. Thirty-seven (80%) and 32 (70%) isolates were not susceptible to ceftolozane-tazobactam and ceftazidime-avibactam, respectively. The clinical response rate was 69% (20/29) with a cefiderocol MIC of ≤1 µg/mL, 69% (9/13) with a cefiderocol MIC of 2 to 4 µg/mL, and 100% (4/4) with an MIC of ≥8 µg/mL, while day 28 all-cause mortality rates were 23% (6/26; MIC ≤ 1 µg/mL), 33% (4/12; MIC, 2 to 4 µg/mL), and 0% (0/4; MIC ≥8 µg/mL), respectively. Cefiderocol was active in vitro against most P. aeruginosa isolated from patients with limited or no alternative therapies. Patients with cefiderocol MICs of 2 to 4 µg/mL did not have significantly worse outcomes than those with MICs of ≤1 µg/mL.

In Vitro Activity of Cefiderocol Against Meropenem-Nonsusceptible Gram-Negative Bacilli with Defined ß-Lactamase Carriage: SIDERO-WT Surveillance Studies, 2014-2019.

We examined the in vitro susceptibility of meropenem-nonsusceptible Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii complex isolates from five consecutive annual SIDERO-WT surveillance studies (2014-2019) to cefiderocol and comparator agents in the context of their carbapenemase carriage. 1,003 Enterobacterales, 1,758 P. aeruginosa, and 2,809 A. baumannii complex isolates from North America and Europe that were meropenem nonsusceptible (CLSI M100, 2022) were molecularly characterized for ß-lactamase content by PCR followed by Sanger sequencing or by whole genome sequencing. Among Enterobacterales, 91.5% of metallo-ß-lactamase (MBL)-producing, 98.4% of KPC-producing, 97.3% of OXA-48 group-producing, and 98.7% of carbapenemase-negative, meropenem-nonsusceptible isolates were cefiderocol susceptible (MIC ≤4 mg/L). Among P. aeruginosa, 100% of MBL-producing, 100% of GES carbapenemase-producing, and 99.8% of carbapenemase-negative, meropenem-nonsusceptible isolates were cefiderocol susceptible (MIC ≤4 mg/L). Among A. baumannii complex, 60.0% of MBL-producing, 95.6% of OXA-23 group-producing, 89.5% of OXA-24 group-producing, 100% of OXA-58 group-producing, and 95.5% of carbapenemase-negative, meropenem-nonsusceptible isolates were cefiderocol susceptible (MIC ≤4 mg/L). Cefiderocol was inactive against A. baumannii complex isolates carrying a PER or VEB ß-lactamase (n = 103; 15.5% susceptible). Ceftazidime-avibactam and ceftolozane-tazobactam were inactive against MBL-carrying and A. baumannii complex isolates; ceftolozane-tazobactam was also inactive against serine carbapenemase-carrying Enterobacterales and P. aeruginosa. In summary, cefiderocol was highly active in vitro against Gram-negative isolates carrying MBLs and serine carbapenemases, as well as carbapenemase-negative, meropenem-nonsusceptible isolates.

In vivo efficacy & resistance prevention of cefiderocol in combination with ceftazidime/avibactam, ampicillin/sulbactam or meropenem using human-simulated regimens versus Acinetobacter baumannii.

OBJECTIVE: Evaluate the in vivo efficacy and resistance prevention of cefiderocol in combination with ceftazidime/avibactam, ampicillin/sulbactam and meropenem using human-simulated regimens (HSR) in the murine infection model. METHODS: In total, 15 clinical A. baumannii were assessed: cefiderocol MICs, 2 mg/L (previously developed resistance on therapy), n = 3; 8 mg/L, n = 2; ≥32 mg/L, n = 10 (including VEB and PER-harbouring isolates). Mice received inactive control, cefiderocol, cefiderocol + ceftazidime/avibactam (C-CZA), cefiderocol + ampicillin/sulbactam (C-SAM) or cefiderocol + meropenem (C-MEM) HSRs. The mean change in log10 cfu/thigh compared with starting inoculum was assessed. Resistance development on treatment was a >4-fold increase in MIC relative control animals. In vitro activities of combinations were assessed by disc stacking. RESULTS: Against cefiderocol-non-susceptible isolates, combinations produced significant kill with C-CZA -3.75 ±â€Š0.37 reduction in log10 cfu/thigh, C-SAM produced -3.55 ±â€Š0.50 and C-MEM produced -2.18 ±â€Š1.75 relative to baseline. Elevated MICs in cefiderocol treated animals occurred in three out of three isolates with MICs of 2 mg/L. Of these isolates, one developed elevated MICs with C-MEM compared with none treated with C-CZA or C-SAM. Disc stacking with C-CZA or C-SAM returned all isolates to at least the CLSI intermediate breakpoint, which may correlate with in vivo efficacy. CONCLUSIONS: Against cefiderocol-non-susceptible isolates, cefiderocol + ceftazidime/avibactam or ampicillin/sulbactam HSR produced in vivo kill against all 12 cefiderocol-non-susceptible isolates. Cefiderocol with ceftazidime/avibactam or ampicillin/sulbactam prevented the development of resistance during treatment against cefiderocol-high-end-susceptible isolates with a propensity for resistance on therapy. These data support the clinical evaluation of cefiderocol with ceftazidime/avibactam or ampicillin/sulbactam against A. baumannii, including multi-drug-resistant isolates.

In vitro antibacterial activities of cefiderocol against Gram-negative clinical strains isolated from China in 2020.

OBJECTIVES: Cefiderocol (CFDC) is a parenteral siderophore cephalosporin that is active against Gram-negative bacteria, including carbapenem-resistant isolates. We report the in vitro activity of CFDC and other antibiotics against 1738 clinical isolates of Gram-negative bacilli (GNB) provided by five medical centres in five provinces of China in 2020 METHODS: Antibiotic susceptibility testing was performed using the Clinical and Laboratory Standards Institute broth microdilution method. RESULTS: Against Pseudomonas aeruginosa and Acinetobacter Spp., the CFDC concentration inhibiting the growth of 90% of the isolates (MIC90) (0.5 µg/mL) was identical and did not change by the carbapenem resistance phenotype. The susceptibility rate of P. aeruginosa and Acinetobacter Spp. to CFDC was high (> 98%) and was similar against isolates with and without meropenem resistance. The MIC of CFDC for all Stenotrophomonas maltophilia isolates (20 isolates) was ≤1 µg/mL and the MIC90 was 0.12 µg/mL. Considerable differences were noted in the susceptibility to CFDC between all tested Enterobacterales isolates and meropenem-non-susceptible Enterobacterales isolates. The MIC90 of CFDC was 1 µg/mL for all tested Enterobacterales isolates and 8 µg/mL for meropenem-non-susceptible Enterobacterales isolates. CONCLUSIONS: CFDC demonstrated potent in vitro activity against a recent collection of clinical isolates, including meropenem-non-susceptible isolates, obtained from medical centres in mainland China.

Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistently Neutropenic Rabbits.

Stenotrophomonas maltophilia is an important cause of pneumonia in immunocompromised patients. Cefiderocol is a parenteral siderophore cephalosporin with potent in vitro activity against S. maltophilia. We evaluated the efficacy of cefiderocol in a neutropenic rabbit model of S. maltophilia pneumonia in comparison to trimethoprim-sulfamethoxazole (TMP-SMX). The cefiderocol area under the plasma drug concentration-time curve extrapolated to 8 h (AUC0-8) was lower (423.0 ± 40.9 µg·h/mL versus 713.6 ± 40.1 µg·h/mL) and clearance higher (252.77 ± 38.9 mL/h/kg versus 142.6 ± 32.9 mL/h/kg) in infected versus noninfected rabbits. We studied a clinical bloodstream S. maltophilia isolate with an MIC of 0.03 µg/mL of cefiderocol. Time spent above the MIC of cefiderocol for the majority of S. maltophilia isolates in rabbits recapitulated the plasma concentration-time profile observed in adult humans at the licensed dose of 2 g given intravenously (i.v.). Experimental groups consisted of 120 mg/kg cefiderocol i.v. every 8 hours (q8h); TMP-SMX, 5 mg/kg i.v. Q12h, and untreated controls (UCs). Treatment was administered for 10 days. Survival in cefiderocol-treated rabbits (87%) was greater than that in TMP-SMX-treated (25%; P < 0.05) and UC (0%; P < 0.05) groups. There was no residual bacterial burden in lung tissue or bronchoalveolar lavage (BAL) fluid in the cefiderocol group. Residual bacterial burden was present in lung tissue and BAL fluid in the TMP-SMX group but was decreased in comparison to UCs (P < 0.001). Lung weights (markers of pulmonary injury) were decreased in cefiderocol-treated versus TMP-SMX (P < 0.001) and UC (P < 0.001) groups. Cefiderocol is highly active in treatment of experimental S. maltophilia pneumonia, laying the foundation for future clinical investigations against this lethal infection in immunocompromised patients.

[Corporate Efforts to Research and Develop Therapeutic Agents for Infectious Diseases That Threaten Human].

Overcoming serious infectious diseases such as malaria, tuberculosis, and other neglected tropical diseases (NTDs) that threaten human life around the world is an important issue in global health. Most of these diseases are concentrated in developing and low-income countries, and in order to reinforce drug discovery activities, pharmaceutical companies are actively promoting industry-academia-government partnerships and utilizing funds to stimulate global health activities. In this presentation, three examples of our drug discovery activities are introduced. The first is participation in the Booster project led by Drugs for Neglected Diseases initiative (DNDi) aimed at creating therapeutic agents for leishmaniasis and Chagas disease, an effort supported by the Global Health Innovative Technology (GHIT) Fund. As domestic and overseas pharmaceutical companies participate in the project and provide their own compounds, it is possible to obtain structure-activity relationship information in a short period of time and improve compound potency. We collaborated with DNDi to create a lead compound from one hit compound, and contributed to further enhancement of its activity. The remaining two are collaborations with academia for the creation of new therapeutic agents or vaccines: a joint research project with Hokkaido University Research Center for Zoonosis Control for emerging viral diseases, and a collaboration with Nagasaki University in malaria. In each case, our researchers were based at the university, establishing close working collaborations with the university researchers. Novel solutions for serious infectious diseases are expected by the combination of the high-level basic research capabilities of academia and the drug discovery know-how and original compound libraries possessed by pharmaceutical companies.

Assessment of sustained efficacy and resistance emergence under human-simulated exposure of cefiderocol against Acinetobacter baumannii using in vitro chemostat and in vivo murine infection models.

Objectives: This study evaluated the sustained kill and potential for resistance development of Acinetobacter baumannii exposed to human-simulated exposure of cefiderocol over 72 h in in vitro and in vivo infection models. Methods: Seven A. baumannii isolates with cefiderocol MICs of 0.12-2 mg/L were tested. The sustained bactericidal activity compared with the initial inoculum and the resistance appearance over 72 h treatment were evaluated in both an in vitro chemostat and an in vivo murine thigh infection model under the human-simulated exposure of cefiderocol (2 g every 8 h as 3 h infusion). Results: In the in vitro model, regrowth was observed against all seven tested isolates and resistance emergence (>2 dilution MIC increase) was observed in five test isolates. Conversely, sustained killing over 72 h and no resistance emergence were observed in six of seven tested isolates in vivo. The mechanism of one resistant isolate that appeared only in the in vitro chemostat studies was a mutation in the tonB-exbB-exbD region, which contributes to the energy transduction on the iron transporters. The resistance acquisition mechanisms of other isolates have not been identified. Conclusions: The discrepancy in the sustained efficacy and resistance emergence between in vitro and in vivo models was observed for A. baumannii. Although the resistance mechanisms in vitro have not been fully identified, sustained efficacy without resistance emergence was observed in vivo for six of seven isolates. These studies reveal the in vivo bactericidal activity and the low potential for development of resistance among A. baumannii evaluated under human-simulated exposures.

Cefiderocol: EUCAST criteria for disc diffusion and broth microdilution for antimicrobial susceptibility testing.

OBJECTIVES: The reproducibility of cefiderocol MIC determination using broth microdilution (BMD) in iron-depleted CAMHB (ID-CAMHB) was investigated, and the EUCAST disc diffusion (DD) method for cefiderocol susceptibility testing was developed and validated against reference BMD. METHODS: Cefiderocol values were determined for wild-type (WT) and non-WT isolates using BMD plates with ID-CAMHB (Thermo Scientific, Oakwood, USA) per EUCAST guidelines. DD was performed using standard EUCAST methodology on unsupplemented Mueller-Hinton agar with cefiderocol 30 µg discs. Control agents were included in all tests. MICs were correlated with zone diameters (ZD), and ZD breakpoints (BP) best corresponding to the MIC BPs were determined. Areas of technical uncertainty (ATU) were included where appropriate. External laboratory validation of cefiderocol DD was performed per the EUCAST SOP 9.2. RESULTS: MIC and ZD distributions for cefiderocol against WT isolates were established. Cefiderocol ZD BPs were set at susceptible ≥22 mm, resistant <22 mm for Enterobacterales and Pseudomonas aeruginosa and ATUs were decided. For Acinetobacter baumannii and Stenotrophomonas maltophilia, ZD cut-off values of ≥17 mm and ≥20 mm corresponded to MIC values of ≤2 and ≤0.5 mg/L, respectively. Cefiderocol ZDs for Escherichia coli ATCC 25922 (target 27 mm) and P. aeruginosa ATCC 27853 (target 26 mm) were within ±3 mm of the target values. For DD, there was no problematic variation between discs, media or laboratories. CONCLUSIONS: DD is a robust and easy-to-perform method for cefiderocol susceptibility testing. For isolates with results in the ATU, an MIC test should be performed to confirm the results.

Cefiderocol for the Treatment of Infections Due to Metallo-B-lactamase-Producing Pathogens in the CREDIBLE-CR and APEKS-NP Phase 3 Randomized Studies.

In the CREDIBLE-CR and APEKS-NP studies, cefiderocol treatment was effective against gram-negative bacteria producing metallo-B-lactamases; rates of clinical cure (70.8% [17/24]), microbiological eradication (58.3% [14/24]), and day 28 all-cause mortality (12.5% [3/24]) compared favorably with comparators of best-available therapy and high-dose meropenem (40.0% [4/10], 30.0% [3/10], and 50.0% [5/10], respectively).

Mechanisms of Reduced Susceptibility to Cefiderocol Among Isolates from the CREDIBLE-CR and APEKS-NP Clinical Trials.

The objective of this study was to characterize isolates with reduced susceptibility to cefiderocol in patients receiving cefiderocol for nosocomial pneumonia or carbapenem-resistant infections in the Phase 3 APEKS-NP and CREDIBLE-CR studies. Susceptibility testing of isolates was conducted at a central laboratory, and post-treatment changes were evaluated according to available breakpoints for cefiderocol. Whole-genome sequencing and multilocus sequence typing were performed for isolates to confirm their origin and identify mutations. Five (APEKS-NP) and nine (CREDIBLE-CR) isolates demonstrated a ≥ 4-fold minimum inhibitory concentration (MIC) increase compared with genetically related baseline isolates; most remained susceptible to cefiderocol despite the ≥4-fold MIC increase. Mutations in ß-lactamases or penicillin-binding protein (PBP) were identified in 4/14 isolates: one Enterobacter cloacae (amino acid [AA] substitution [A313P] in ACT-17); two Acinetobacter baumannii (one PBP3 AA substitution [H370Y], one with OXA-23 substitutions [N85I and P225S]); and one Pseudomonas aeruginosa (PDC-30 [4AA deletion "TPMA" position 316-319]). Cloning experiments using isogenic Escherichia coli strains containing wild-type and those mutant cephalosporinase enzymes show that the mutant enzymes may contribute to decreased susceptibility to cefiderocol. Pharmacokinetic data were available for nine patients, for whom cefiderocol exposures exceeded 100% fT > 4 × MIC. No clear pattern between mutations and development or extent of MIC increases was observed. No mutations were identified in genes related to iron transport, including fiu, cirA, piuA/C, and pirA, among recovered Gram-negative isolates. Clinicaltrials.gov: APEKS-NP: NCT03032380; CREDIBLE-CR: NCT02714595.

In vitro activity of the novel siderophore cephalosporin, cefiderocol, in Gram-negative pathogens in Europe by site of infection.

OBJECTIVES: We assessed the activity of the novel siderophore cephalosporin, cefiderocol and selected other antibacterial agents against Gram-negative bacterial isolates in Europe. METHODS: Isolates were obtained between 2013 and 2018 from European countries participating in the SIDERO-WT and SIDERO-Proteeae multinational surveillance studies. Isolates were categorised by infection site, focusing on bloodstream infections, hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), complicated intra-abdominal infections and complicated urinary tract infections. Cefiderocol activity was compared with ceftazidime-avibactam, ceftolozane-tazobactam, colistin and meropenem using standard susceptibility testing methods. European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints were used to interpret susceptibility data. RESULTS: Isolates (n = 20 911) were collected from 145 sites in 24 countries in Europe, the highest proportion (34%) being from patients with HABP/VABP. Enterobacterales (66.6% of isolates) were more frequent than glucose non-fermenting species (33.4%) overall, with some differences between infection sites. Across all infection sites, the MIC50/MIC90 for cefiderocol was ≤0.5/≤2 mg/L for Enterobacter spp., ≤0.25/<2 mg/L for Klebsiella spp., 0.12/2 mg/L for Acinetobacter spp., ≤0.25/1 mg/L for Pseudomonas aeruginosa and ≤0.12/≤0.5 mg/L for Stenotrophomonas maltophilia. Across all infection sites, cefiderocol MICs were ≤2 mg/L for ≥96% of Enterobacter spp., ≥95% of Klebsiella spp., ≥90% of Acinetobacter spp. and ≥99% of Pseudomonas aeruginosa and Stenotrophomonas maltophilia isolates. Cefiderocol maintained high activity in carbapenem-resistant isolates, and the difference in activity between carbapenem-resistant (percentage susceptibility at EUCAST breakpoint: E. coli 77.8%, Klebsiella spp. 69.2%, Pseudomonas aeruginosa 97.5%, Acinetobacter spp. 90.7%, Stenotrophomonas maltophilia 99.6%) and carbapenem-susceptible (percentage susceptibility at EUCAST breakpoint: E. coli 99.4%, Klebsiella spp. 98.0%, Pseudomonas aeruginosa 99.7%, Acinetobacter spp. 94.9%) isolates was lower for cefiderocol than other agents. CONCLUSIONS: Cefiderocol had excellent activity against all Gram-negative species, independent of key infection site and carbapenem MIC. Cefiderocol is a useful addition to the therapeutic options available for these difficult-to-treat infections.

In Vitro Susceptibility of Gram-Negative Pathogens to Cefiderocol in Five Consecutive Annual Multinational SIDERO-WT Surveillance Studies, 2014 to 2019.

We report in vitro susceptibility data from five consecutive annual SIDERO-WT surveillance studies (2014 to 2019) for cefiderocol and comparators tested against Gram-negative clinical isolates from North America and Europe. CLSI broth microdilution was used to determine MICs for Enterobacterales (n = 31,896), Pseudomonas aeruginosa (n = 7,700), Acinetobacter baumannii complex (n = 5,225), Stenotrophomonas maltophilia (n = 2,030), and Burkholderia cepacia complex (n = 425). MICs were interpreted by CLSI-approved clinical breakpoints (February 2021). Cefiderocol inhibited 99.8, 96.7, 91.6, and 97.7% of all Enterobacterales, meropenem-nonsusceptible, ceftazidime-avibactam-nonsusceptible, and ceftolozane-tazobactam-nonsusceptible isolates, respectively, at ≤4 µg/mL (susceptible breakpoint). Cefiderocol inhibited 99.9, 99.8, 100, and 99.8% of all P. aeruginosa, meropenem-nonsusceptible, ceftazidime-avibactam-nonsusceptible, and ceftolozane-tazobactam-nonsusceptible isolates, respectively, at ≤4 µg/mL (susceptible breakpoint). Cefiderocol inhibited 96.0% of all A. baumannii complex isolates and 94.2% of meropenem-nonsusceptible isolates at ≤4 µg/mL (susceptible breakpoint) and 98.6% of S. maltophilia isolates at ≤1 µg/mL (susceptible breakpoint). B. cepacia complex isolates were tested with a MIC50 of ≤0.03 µg/mL and MIC90 of 0.5 µg/mL. Annual cefiderocol percent susceptible rates for Enterobacterales (North America range, 99.6 to 100%/year; Europe range, 99.3 to 99.9%/year) and P. aeruginosa (North America range, 99.8 to 100%; Europe range, 99.9 to 100%) were unchanged from 2014 to 2019. Annual percent susceptible rates for A. baumannii complex demonstrated sporadic, nondirectional differences (North America range, 97.5 to 100%; Europe range, 90.4 to 97.5%); the wider range for Europe (∼7%) was due to isolates from Russia. Annual percent susceptible rates for S. maltophilia showed minor, nondirectional differences (North America range, 96.4 to 100%; Europe range, 95.6 to 100%). We conclude that clinical isolates of Enterobacterales (99.8% susceptible), P. aeruginosa (99.9%), A. baumannii (96.0%), and S. maltophilia (98.6%) collected in North America and Europe from 2014 to 2019 were highly susceptible to cefiderocol.