P44 Nosocomial neurosurgical meningitis due to XDR Pseudomonas aeruginosa: clinical experience with cefiderocol

Abstract

Background Carbapenem resistance due to MBL production is relatively uncommon in Pseudomonas aeruginosa infections in the UK. We report a case of post-operative meningitis caused by a New-Delhi MBL-producing (NDM-1) strain, outlining the microbiological and management challenges. Patient case The patient was admitted to intensive care after craniotomy and evacuation for an intracerebral haemorrhage. Three weeks later she was febrile due to nosocomial meningitis. Purulent material evacuated from extradural and subdural spaces cultured P. aeruginosa, along with blood cultures and CSF. Susceptibility testing as per EUCAST methodology indicated the isolate was resistant to all β-lactams, aminoglycosides and quinolones but susceptible to colistin. Susceptibility to cefiderocol by disc diffusion was in the area of technical uncertainty at 21 mm (S≥22 mm). Immunochromatographic flow testing (CARBA5 NG Biotech) detected an NDM carbapenemase. WGS (Illumina) confirmed the presence of blaNDM-1 and a plethora of AMR genes responsible for the XDR phenotype {cephalosporins (blaPDC-10, blaOXA-488), aminoglycosides [aph(3')-VIa], quinolones (crpP), macrolides [mph(E), msr(E)], phenicols (catB7) and fosfomycin (fosA)}. No mutations in PBPs associated with resistance to β-lactams or iron acquisition systems involved in uptake of siderophore conjugated antibiotics were identified. The isolate belonged to ST1047, serotype 07, previously identified as a high-risk epidemic clone originating in Myanmar. Results Treatment was commenced with IV and intrathecal colistin as well as IV cefiderocol (Figure 1); a novel siderophore cephalosporin licensed for Gram-negative infections with limited treatment options. No synergy between the two drugs could be demonstrated in chequerboard assays. Although CSF sterility was achieved on three subsequent cultures with clinical response, the patient sadly died due to the underlying intracerebral injury. Four other patients subsequently became colonized with this strain and infection control measures (twice weekly screening of all patients, environmental cleaning, water testing, isolation of cases) were instituted, bringing the outbreak under control. Variable number tandem repeat analysis linked these strains to that of another patient discharged from the unit 9 months prior, but not previously reported in the UK. Conclusions The first problem encountered was a lack of evidence for the CNS penetration of cefiderocol and efficacy in the treatment of meningitis. The external ventricular drain required to administer intrathecal colistin enabled us to monitor CSF cefiderocol levels. Five CSF samples were shipped at −80°C for analysis in Germany by mass spectrometry. CSF cefiderocol levels of 1.22 μg/mL, 1.34 μg/mL, 2.39 μg/mL, 3.53 μg/mL and 3.90 μg/mL were disappointingly close to the pharmacodynamic breakpoint of 2 μg/mL and only available after treatment withdrawal. Dosing of cefiderocol was initially cautious starting at 1 g/8 h due to a creatinine clearance of 53 mL/min but later increased to 1.5 g/8 h. Further dose increases guided by serum and CSF monitoring could feasibly lead to therapeutic CSF cefiderocol levels. Clinical and pharmacological studies are needed in this area. To our knowledge this is the first attempt to treat a case of XDR neurosurgical meningitis using cefiderocol with precision treatment and achieving microbiological cure.

Clinical Cure of a Difficult-to-Treat Resistant Pseudomonas aeruginosa Ventriculitis Using Cefiderocol: A Case Report and Literature Review

“…Thus, Luque-Paz et al prescribed 2 g IV every 6 hours through 3-hour extended infusion after a 2-g bolus, Stevenson et al 1 g IV 4 times daily, and in our case 2 g IV 4 times daily through 3-hour extended infusion. These 4 well-known patients with complex meningitis have received combined treatment with colistin [ 9 , 11 , 12 ], but only our patient and Meschiari et al’s patient have recovered.…”

“…Recently, Luque-Paz et al published a case report of an MDR P. aeruginosa ventriculitis treated with cefiderocol, in which they measured CSF trough drug levels that were similar to levels found in our work, but peak drug levels were unknown [ 12 ]. Concurrently, another patient with a DTR P. aeruginosa ventriculitis was published with measured CSF cefiderocol levels [ 11 ]. The CSF levels found in both cases and ours were in the same range (1.22–24.4 μg/mL), although the doses of cefiderocol used in each case were different [ 11 , 12 ].…”

“…Concurrently, another patient with a DTR P. aeruginosa ventriculitis was published with measured CSF cefiderocol levels [ 11 ]. The CSF levels found in both cases and ours were in the same range (1.22–24.4 μg/mL), although the doses of cefiderocol used in each case were different [ 11 , 12 ]. Thus, Luque-Paz et al prescribed 2 g IV every 6 hours through 3-hour extended infusion after a 2-g bolus, Stevenson et al 1 g IV 4 times daily, and in our case 2 g IV 4 times daily through 3-hour extended infusion.…”

“…However, there are inconclusive data on its use in CNS infections; clinical experience in treating these infections is limited [ 9 ], and the article from Kawaguchi et al on pharmacokinetics and pharmacodynamics of cefiderocol does not even mention CNS infections [ 10 ]. Recently, a few sporadic cases of ventriculitis by DTR P. aeruginosa have been reported [ 11 , 12 ], in which cefiderocol was used as treatment, being only effective in some of them. As we are already aware, ventriculitis is a difficult-to-treat CNS infection associated with poor clinical outcomes [ 13 ], with an even worse prognosis if it is caused by a DTR bacteria [ 14 , 15 ].…”

Treatment with cefiderocol in K. pneumoniae KPC nosocomial external ventricular drainage meningitis: A brief report

“…Therapeutic drug monitoring (TDM) demonstrated a good CSF concentration. However, clinical success was achieved with lower dosages than recommended (started at 1 g every 8 hours and later increased to 1.5 g every 8 hours) [13]. In another real-life case study, post-craniotomy meningitis caused by resistant P. aeruginosa was treated with FDC.…”