Adjunctive Cefiderocol Treats XDR P aeruginosa Endocarditis

After the failure of conventional therapeutics, cefiderocol, a novel parenteral siderophore cephalosporin, may be successful in patients with persistently bacteremic healthcare-associated native aortic valve endocarditis, according to a study recently published in Clinical Infectious Diseases.

The emergence of multiresistant and extremely resistant gram-negative pathogens presents a significant global health challenge and underscores the urgent need for new antibiotics. Cefiderocol is currently being developed to treat serious infections, including those resulting from carbapenem-resistant gram-negative strains. Cefiderocol has a unique mechanism of cell entry via bacterial iron transport channels that allows it to efficiently enter gram-negative bacteria, even when accumulation of other agents is reduced as a result of porin channel loss and increased expression of efflux pumps. 

This antibiotic has good stability to all classes of β-lactamases. The combination of properties allows potent antibacterial activity against a variety of Enterobacteriaceae and nonfermenting gram-negative bacteria, but activity against gram-positive bacteria and anaerobic bacteria is poor. Cefiderocol has been assessed in early-phase clinical trials for safety, tolerability, and pharmacodynamic behavior; has completed a phase 2 study and been shown to be effective and safe for the treatment of complicated urinary tract infection; and is currently being evaluated in phase 3 studies. The developers of cefiderocol were approached to assist with treatment of a patient, as described here.

In October 2017, a 78-year-old woman was transferred to the intensive care unit at London Bridge Hospital from Kuwait for specialist urologist and respiratory management as a result of complications of spontaneous ureteric hematoma with secondary hydronephrosis. On arrival, the patient was ventilated and received intermittent hemofiltration without hemodynamic support or treatment antimicrobials. Blood cultures taken at admission grew extremely drug-resistant (XDR)-Pseudomonas aeruginosa  that was susceptible to gentamicin, amikacin, and colistin, but resistant to all β-lactams and quinolone antibiotics. The patient was started on colistin empirically, together with intermittent gentamicin based on serum levels.

The results of a transthoracic echocardiogram showed a thickened aortic valve. A blood culture was obtained when the patient later become clinically septic, and grew P aeruginosa. Therefore, gentamicin was stopped on day 5 and replaced with meropenem. While the patient was undergoing assessment for aortic valve surgery, blood cultures were negative; however, there was significant neurological deterioration with a computed tomography scan, and soon after, blood cultures became positive again. Therefore, cefiderocol was administered on day 83 while continuing meropenem and colistin; aortic valve replacement was performed on day 85. Blood culture taken before the first cefiderocol dose remained positive, but a blood culture taken after the sixth dose was negative after 5 days of culture. After surgery, meropenem was stopped a week after surgery; the cefiderocol/colistin combination was continued 4 weeks after surgery. Multiple blood cultures after surgery and after stopping all antibiotics were negative up to day 275 before the patient was transferred back to Kuwait. A serious adverse event of neutropenia was reported, and either colistin or cefiderocol was considered the most likely potential cause.

Overall, the study authors concluded that, “This article presents successful adjunctive use of cefiderocol for a patient with persistently bacteremic healthcare-associated native aortic valve endocarditis due to an [extended spectrum beta-lactamase]-positive P. aeruginosa susceptible in vitro only to colistin, following failure of conventional therapeutic options.”

Reference

Edgeworth JD, Merante D, Patel S, et al. Compassionate use of cefiderocol as adjunctive treatment of native aortic valve endocarditis due to XDR-Pseudomonas aeruginosa [published online November 12, 2018]. Clin Infect Dis. doi: 10.1093/cid/ciy963/5174241