In Vitro Pharmacodynamic Analyses Help Guide the Treatment of Multidrug-Resistant Enterococcus faecium and Carbapenem-Resistant Enterobacter cloacae Bacteremia in a Liver Transplant Patient

Abstract

Background Infections due to multidrug-resistant pathogens are particularly deadly and difficult to treat in immunocompromised patients, where few data exist to guide optimal antimicrobial therapy. In the absence of adequate clinical data, in vitro pharmacokinetic (PK)/pharmacodynamic (PD) analyses can help to design treatment regimens that are bactericidal and may be clinically effective. Methods We report a case in which in vitro pharmacodynamic analyses were utilized to guide the treatment of complex, recurrent bacteremias due to vancomycin-, daptomycin-, and linezolid-resistant Enterococcus faecium and carbapenem-resistant Enterobacter cloacae complex in a liver transplant patient. Results Whole-genome sequencing revealed unique underlying resistance mechanisms and explained the rapid evolution of phenotypic resistance and complicated intrahost genomic dynamics observed in vivo. Performing this comprehensive genotypic and phenotypic testing and time-kill analyses, along with knowledge of institution and patient-specific factors, allowed us to use precision medicine to design a treatment regimen that maximized PK/PD. Conclusions This work provides a motivating example of clinicians and scientists uniting to optimize care in the era of escalating antimicrobial resistance.

Inadequate Cerebrospinal Fluid Concentrations of Available Salvage Agents Further Impedes the Optimal Treatment of Multidrug-Resistant Enterococcus faecium Meningitis and Bacteremia

“…Currently, no in vitro or in vivo PK/PD data are available to guide their use against VREf, and only eravacycline has data regarding the CNS penetration in rabbits which was virtually zero [ 39 ]. Finally, the current study expands on our groups’ previous work by evaluating additional combination therapies against daptomycin and linezolid-resistant VREf in time-kill analyses and confirming the sustainability and utility of this clinician–scientist collaboration [ 4 ].…”

“…Time-kill experiments were performed in triplicate on the same day as previously described [ 4 ] against the VREf isolate cultured from the CSF on hospital day 33. Analytical grade gentamicin, oritavancin, and tigecycline (Sigma-Aldrich, St. Louis, MO, USA), along with tedizolid, dalfopristin, and quinupristin (pristinamycin-IA) (MedChemExpress, Monmouth Junction, NJ, USA) were obtained commercially.…”

“…In addition, their proclivity for vulnerable hosts, predilection for immune-privileged body sites, and complex genotypic–phenotypic relationships have caused them to emerge as one of the most formidable pathogens of the current post-antibiotic era [ 3 ]. Furthermore, the emergence of resistance to current first-line treatment agents such as daptomycin and linezolid along with the paucity of high-quality pre-clinical or clinical data supporting alternative treatment regimens has forced clinicians to rely on data from in vitro models, retrospective studies, and case reports when faced with treating extensively resistant VREf infections, particularly in immunocompromised patients [ 4 ].…”

“…This unfortunate combination of antimicrobial resistance, lack of clinical data and clinician experience, and the dearth of available effective treatment options presents a unique opportunity for collaboration between clinicians and researchers. These collaborations have been employed successfully, especially recently, against a variety of difficult-to-treat pathogens in complex clinical scenarios, highlighting the need for these types of partnerships to optimize therapy and achieve precision medicine [ 4 , 7 , 8 , 9 , 10 ]. Herein, we present a case of an immunocompromised stem cell transplant patient with persistent, extremely drug resistant VREf bacteremia and meningitis treated in collaboration between clinicians and scientists via the use of unique therapeutic drug monitoring and in vitro pharmacokinetic/pharmacodynamic (PK/PD) analyses.…”

Diversity of the microbial community and antioxidant activity during fermentation of red raspberry Enzymes

“…In addition, certain genera, such as Enterobacter , can cause recurrent bacteremia with strong antibiotic resistance. The production environment may become a secondary pollution source of Enterobacter (Wenzler et al., 2020), which is worth considerable attention and should not be regarded merely as a coincidence.…”