Acinetobacter baumannii and Cefiderocol, between Cidality and Adaptability

Stracquadanio, Stefano; Bonomo, Carmelo; Marino, Andrea; Bongiorno, Dafne; Privitera, Grete Francesca; Bivona, Dalida Angela; Mirabile, Alessia; Bonacci, Paolo Giuseppe; Stefani, Stefania

doi:10.1128/spectrum.02347-22

Cited by 28 publications

(35 citation statements)

References 33 publications

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“…Given the increasing prevalence of colistin-resistant strains, a reassessment of current therapeutic approaches, including alternatives to traditional antibiotics therapies, is strongly recommended. Promising results have been shown in vitro for cefiderocol (a molecule with an innovative mode of action), intravenous fosfomycin (in combination with cefiderocol), and combination therapy with sulbactam–durlobactam [ 161 , 162 , 163 ].…”

Section: Discussionmentioning

confidence: 99%

Colistin Resistance in Acinetobacter baumannii: Molecular Mechanisms and Epidemiology

Novović

Jovčić

2023

Antibiotics

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Acinetobacter baumannii is recognized as a clinically significant pathogen causing a wide spectrum of nosocomial infections. Colistin was considered a last-resort antibiotic for the treatment of infections caused by multidrug-resistant A. baumannii. Since the reintroduction of colistin, a number of mechanisms of colistin resistance in A. baumannii have been reported, including complete loss of LPS by inactivation of the biosynthetic pathway, modifications of target LPS driven by the addition of phosphoethanolamine (PEtN) moieties to lipid A mediated by the chromosomal pmrCAB operon and eptA gene-encoded enzymes or plasmid-encoded mcr genes and efflux of colistin from the cell. In addition to resistance to colistin, widespread heteroresistance is another feature of A. baumannii that leads to colistin treatment failure. This review aims to present a critical assessment of relevant published (>50 experimental papers) up-to-date knowledge on the molecular mechanisms of colistin resistance in A. baumannii with a detailed review of implicated mutations and the global distribution of colistin-resistant strains.

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Section: Discussionmentioning

confidence: 99%

Colistin Resistance in Acinetobacter baumannii: Molecular Mechanisms and Epidemiology

Novović

Jovčić

2023

Antibiotics

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“…According to this assumption, ID1 and ID3 would have had f C trough /MIC ≥12 ( Table 2 ). Furthermore, the presence of a f C trough /MIC ≥ 4 has been suggested recently as an effective target to achieve microbiological cure and reduce the emergence of multidrug resistance while treating DTR-AB [ 25 ]. ID2 had f C trough /MIC = 3.0.…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, we only speculated about the protein binding of cefiderocol, and the precise f C trough concentration has not been calculated in this case series. Recently, it has been demonstrated that following increasing exposure to cefiderocol, there is the possibility of selection of some subpopulations of DTR-AB-harboring cefiderocol resistance, a phenomenon known as heteroresistance [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic of Cefiderocol in Critically Ill Patients Receiving Renal Replacement Therapy: A Case Series

et al. 2022

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Background: Cefiderocol is a novel parenteral siderophore cephalosporin, demonstrating enhanced activity against multidrug-resistant (MDR) Gram-negative bacteria and difficult-to-treat Acinetobacter baumannii (DTR-AB). Plasma-free trough concentration (fCtrough) over the minimum inhibitory concentration (MIC) was reported as the best pharmacokinetic parameter to describe the microbiological efficacy of cefiderocol. Materials and methods: We retrospectively described the pharmacokinetic and pharmacodynamic profile of three critically ill patients admitted to the intensive care unit, receiving cefiderocol under compassionate use to treat severe DTR-AB infections while undergoing continuous venovenous haemofiltration. Cefiderocol was administrated at a dosage of 2 g every 8 h infused over 3 h. Therapeutic drug monitoring (TDM) was assessed at the steady state. Cthrough was evaluated by assuming a plasma protein binding of 58.0%. The fCmin/MIC was calculated assuming a cefiderocol MIC equal to the PK-PD breakpoint of susceptibility ≤ 2. The association between the PK/PD parameters and microbiological outcome was assessed. Results: fCtrough/MIC were >12 in 2 patients and 2.9 in the 1 who rapidly recovered from renal failure. Microbiological cure occurred in 3/3 of patients. None of the 3 patients died within 30 days. Conclusions: A cefiderocol dosage of 2 g q8 h in critically ill patients with AKI undergoing CVVH may bring about a very high plasma concentration, corresponding to essentially 100% free time over the MIC for DTR-AB.

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“…The number of A. junii isolates that include both antibiotic susceptibility and genome sequence information in public databases is rare. Additionally, the colistin susceptibility level of AJ6079 was close to the proposed resistance breakpoints and the phenome has been characterized as heteroresistance subpopulations in a previous study [ 23 ]. The method we used to determine MICs could not distinguish whether the strain was heteroresistant to colistin.…”

Section: Resultsmentioning

confidence: 66%

Emergence of Colistin-Resistant Acinetobacter junii in China

et al. 2022

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The increasing number of multidrug-resistant Gram-negative bacteria presents a serious threat to global health. However, colistin-resistant Acinetobacter junii has rarely been reported. We identified a colistin-resistant A. junii clinical isolate, AJ6079, in blood. The colony of AJ6079 presented a dry phenotype, and it was difficult to form a bacterial suspension, whilst transmission electron microscopy revealed that AJ6079 possessed a thick outer membrane. The phenotypic and genomic comparisons were conducted with one colistin-susceptible A. junii, which had the same antibiotic susceptibility profile except for colistin, and had the same KL25 capsule biosynthesis locus. The AJ6079 exhibited a slower growth rate, indicating that colistin-resistant A. junii possesses a higher fitness cost. The genome of AJ6079 had a G+C content of 38.7% and contained one 3,362,966 bp circular chromosome with no plasmid or mobile colistin resistance (mcr) gene. Comparative genomic analysis revealed that the AJ6079 contained several previously unreported point mutations in colistin-resistance-related genes involving amino acid substitutions in PmrB (N5K, G147C), LpxA (I107F, H131Y), and LpxD (F20I, K263R), which might be correlated with colistin resistance in A. junii. Further research is needed for verification as the genetic background was not exactly the same between the two isolates.

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Acinetobacter baumannii and Cefiderocol, between Cidality and Adaptability

Cited by 28 publications

References 33 publications

Colistin Resistance in Acinetobacter baumannii: Molecular Mechanisms and Epidemiology

Colistin Resistance in Acinetobacter baumannii: Molecular Mechanisms and Epidemiology

Pharmacokinetic of Cefiderocol in Critically Ill Patients Receiving Renal Replacement Therapy: A Case Series

Emergence of Colistin-Resistant Acinetobacter junii in China

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