TY - JOUR
AU - Jacob, Jesse T
AB - Infections with carbapenem-resistant Enterobacterales (CRE) are associated with mortality rates of up to 50% in the USA.1 Optimal empirical treatment remains challenging and requires collaboration between microbiologists, clinicians and sometimes translational researchers as traditional susceptibility testing methods may fail to detect clinically meaningful resistance. Here we describe a patient with Klebsiella pneumoniae bloodstream infection where heteroresistance to cefiderocol may have contributed to clinical failure despite seemingly appropriate antimicrobial therapy. Heteroresistance is a phenomenon whereby an established minority subpopulation of resistant bacteria within the larger community proliferates under specific antibiotic pressure. These subpopulations are often infrequent enough that they are not detected using standard antimicrobial susceptibility testing. After prolonged exposure to the specific antibiotic, the resistant subpopulation expands, and clinically meaningful resistance can occur. Transient and unstable gene amplification or mutations that revert if antibiotic pressure is withdrawn may drive the resistant subpopulation.2 Recently, cefiderocol heteroresistance has been reported in CRE, but the clinical implications are unresolved.3 Our findings raise concern that the increased mortality observed with cefiderocol use in trials such as CREDIBLE-CR might be attributed to undetected heteroresistance despite reported susceptibility using conventional testing.3 A man in his 50s with multiple comorbidities including chronic haemodialysis and extensive recent healthcare exposures was transferred to our hospital’s ICU with septic shock from a long-term acute care hospital. Admission blood cultures were positive for K. pneumoniae and attributed to two tunnelled haemodialysis catheters (a functional femoral site and a dysfunctional internal jugular site). Antimicrobial susceptibility testing using a VITEK®2 GN74 card (bioMérieux, Durham, NC, USA) showed resistance to meropenem and all other tested first-line agents (Table 1). The patient was empirically treated with colistin, ceftazidime/avibactam and aztreonam, and blood cultures cleared within 24 h. The isolate was susceptible to cefiderocol using disc diffusion (Liofilchem Inc., Waltham, MA, USA). Gradient diffusion revealed susceptibility to tigecycline. Based on these results, the patient’s antibiotics were changed to cefiderocol and tigecycline, and he continued to improve clinically. Real-time PCR and subsequent WGS of the K. pneumoniae isolate detected New Delhi MBL-5 (NDM-5; Table S1, available as Supplementary data at JAC Online). Because of limited intravascular access, the dysfunctional internal jugular haemodialysis catheter was exchanged over a guidewire for a triple lumen catheter on day 7. On day 8 of therapy, the patient was noted to have new thrombocytopenia attributed to tigecycline, which was stopped. He completed the final 6 days of his planned 14 day course with cefiderocol monotherapy. His femoral catheter was exchanged for another haemodialysis catheter on day 12 of antibiotic treatment (Figure S1). Ten days after completing therapy, he became hypotensive and blood cultures grew K. pneumoniae with an identical antibiogram to the initial isolate and 99.995% similarity by WGS, although with the new isolate missing an rmtB1 16S methyltransferase noted in the initial isolate (Table S1). CT of the abdomen showed multiple liver abscesses, not present on prior imaging. The largest abscess was drained and a culture grew K. pneumoniae with susceptibility identical to that of the blood isolate. Testing of both blood isolates in our research laboratory showed heteroresistance to cefiderocol, but susceptibility to aztreonam/avibactam, using population analysis profiling (Table 1, Supplementary Methods and Figure S2). After changing therapy to ceftazidime/avibactam and aztreonam, and removing the recently replaced femoral haemodialysis catheter, the patient’s bacteraemia cleared, although he remained critically ill. Given his overall prognosis, the patient’s family elected to transition to hospice care. Table 1. Susceptibility testing of the K. pneumoniae isolates . K. pneumoniae, blood culture, admission . K. pneumoniae, blood culture, hospital day 32 . MIC (mg/L) . interpretation . MIC (mg/L) . interpretation . VITEK®2 GN74  amikacin ≥64 R ≥64 R  ampicillin/sulbactam ≥32/16 R ≥32/16 R  aztreonam ≥64 R ≥64 R  cefazolin ≥64 R ≥64 R  cefepime ≥64 R ≥64 R  cefoxitin ≥64 R ≥64 R  ceftazidime ≥64 R ≥64 R  ceftriaxone ≥64 R ≥64 R  gentamicin ≥16 R ≥16 R  levofloxacin ≥8 R ≥8 R  meropenem ≥16 R ≥16 R  piperacillin/tazobactam ≥128/4 R ≥128/4 R  tobramycin ≥16 R ≥16 R  trimethoprim/sulfamethoxazole ≥16/304 R ≥16/304 R Gradient diffusion  ceftazidime/avibactam ≥256 R ≥256 R  ceftolozane/tazobactam ≥256 R ≥256 R  meropenem/vaborbactam ≥256 R 24a R  tigecyclineb 1.5 S 4 I Disc diffusion  cefiderocol 18 mm S PAP testing  cefiderocol ≥32 HR ≥32 HR  aztreonam ≥64 R ≥64 R  ceftazidime/avibactam ≥64/4 R ≥64/4 R  aztreonam/avibactam 4/4 S 4/4 S . K. pneumoniae, blood culture, admission . K. pneumoniae, blood culture, hospital day 32 . MIC (mg/L) . interpretation . MIC (mg/L) . interpretation . VITEK®2 GN74  amikacin ≥64 R ≥64 R  ampicillin/sulbactam ≥32/16 R ≥32/16 R  aztreonam ≥64 R ≥64 R  cefazolin ≥64 R ≥64 R  cefepime ≥64 R ≥64 R  cefoxitin ≥64 R ≥64 R  ceftazidime ≥64 R ≥64 R  ceftriaxone ≥64 R ≥64 R  gentamicin ≥16 R ≥16 R  levofloxacin ≥8 R ≥8 R  meropenem ≥16 R ≥16 R  piperacillin/tazobactam ≥128/4 R ≥128/4 R  tobramycin ≥16 R ≥16 R  trimethoprim/sulfamethoxazole ≥16/304 R ≥16/304 R Gradient diffusion  ceftazidime/avibactam ≥256 R ≥256 R  ceftolozane/tazobactam ≥256 R ≥256 R  meropenem/vaborbactam ≥256 R 24a R  tigecyclineb 1.5 S 4 I Disc diffusion  cefiderocol 18 mm S PAP testing  cefiderocol ≥32 HR ≥32 HR  aztreonam ≥64 R ≥64 R  ceftazidime/avibactam ≥64/4 R ≥64/4 R  aztreonam/avibactam 4/4 S 4/4 S S, susceptible; I, intermediate; R, resistant; HR, heteroresistant; PAP, population analysis profiling. Interpretations reported using CLSI breakpoints. a True MIC reported. b Tigecycline is reported using FDA breakpoints. Open in new tab Table 1. Susceptibility testing of the K. pneumoniae isolates . K. pneumoniae, blood culture, admission . K. pneumoniae, blood culture, hospital day 32 . MIC (mg/L) . interpretation . MIC (mg/L) . interpretation . VITEK®2 GN74  amikacin ≥64 R ≥64 R  ampicillin/sulbactam ≥32/16 R ≥32/16 R  aztreonam ≥64 R ≥64 R  cefazolin ≥64 R ≥64 R  cefepime ≥64 R ≥64 R  cefoxitin ≥64 R ≥64 R  ceftazidime ≥64 R ≥64 R  ceftriaxone ≥64 R ≥64 R  gentamicin ≥16 R ≥16 R  levofloxacin ≥8 R ≥8 R  meropenem ≥16 R ≥16 R  piperacillin/tazobactam ≥128/4 R ≥128/4 R  tobramycin ≥16 R ≥16 R  trimethoprim/sulfamethoxazole ≥16/304 R ≥16/304 R Gradient diffusion  ceftazidime/avibactam ≥256 R ≥256 R  ceftolozane/tazobactam ≥256 R ≥256 R  meropenem/vaborbactam ≥256 R 24a R  tigecyclineb 1.5 S 4 I Disc diffusion  cefiderocol 18 mm S PAP testing  cefiderocol ≥32 HR ≥32 HR  aztreonam ≥64 R ≥64 R  ceftazidime/avibactam ≥64/4 R ≥64/4 R  aztreonam/avibactam 4/4 S 4/4 S . K. pneumoniae, blood culture, admission . K. pneumoniae, blood culture, hospital day 32 . MIC (mg/L) . interpretation . MIC (mg/L) . interpretation . VITEK®2 GN74  amikacin ≥64 R ≥64 R  ampicillin/sulbactam ≥32/16 R ≥32/16 R  aztreonam ≥64 R ≥64 R  cefazolin ≥64 R ≥64 R  cefepime ≥64 R ≥64 R  cefoxitin ≥64 R ≥64 R  ceftazidime ≥64 R ≥64 R  ceftriaxone ≥64 R ≥64 R  gentamicin ≥16 R ≥16 R  levofloxacin ≥8 R ≥8 R  meropenem ≥16 R ≥16 R  piperacillin/tazobactam ≥128/4 R ≥128/4 R  tobramycin ≥16 R ≥16 R  trimethoprim/sulfamethoxazole ≥16/304 R ≥16/304 R Gradient diffusion  ceftazidime/avibactam ≥256 R ≥256 R  ceftolozane/tazobactam ≥256 R ≥256 R  meropenem/vaborbactam ≥256 R 24a R  tigecyclineb 1.5 S 4 I Disc diffusion  cefiderocol 18 mm S PAP testing  cefiderocol ≥32 HR ≥32 HR  aztreonam ≥64 R ≥64 R  ceftazidime/avibactam ≥64/4 R ≥64/4 R  aztreonam/avibactam 4/4 S 4/4 S S, susceptible; I, intermediate; R, resistant; HR, heteroresistant; PAP, population analysis profiling. Interpretations reported using CLSI breakpoints. a True MIC reported. b Tigecycline is reported using FDA breakpoints. Open in new tab Cefiderocol monotherapy is an option recommended in recent society guidance documents; however, these recommendations are based on limited clinical and in vitro data, and prior reports have raised concerns regarding cefiderocol’s efficacy in invasive, highly resistant Gram-negative infections.3,4 Given that these isolates harboured NDM-5, susceptibility to aztreonam combined with avibactam was not surprising.5 The resistance of aztreonam, a monobactam, to hydrolysis by MBLs may be due to poor binding affinity.6 However, avibactam is also required to protect aztreonam from inactivation by other β-lactamases frequently found in organisms harbouring MBLs. In this case, the combination of aztreonam and avibactam may have been superior to cefiderocol monotherapy. Cefiderocol is a relatively novel and unique cephalosporin developed for highly resistant Gram-negative bacteria. Interpreting microbiological testing for novel antibiotics such as cefiderocol can prove challenging as the tested isolate is considered susceptible using CLSI breakpoints for cefiderocol,7 but resistant using EUCAST breakpoints.8 Results from the CREDIBLE-CR trial showed increased mortality in Acinetobacter spp. infections and raised concern for the use of cefiderocol against some Gram-negative infections.9 Heteroresistance has been postulated as a potential mechanism for these clinical failures.3 Our case adds further evidence for concern and exemplifies the potential clinical importance of heteroresistance to cefiderocol. Cefiderocol heteroresistance, the lack of optimal source control or a combination of both may have led to this patient’s clinical outcome. This case illustrates the synergy in using both the clinical and research laboratories in providing data that can inform patient care and suggests further investigations are needed into the efficacy of cefiderocol as monotherapy for MDR organisms, with particular attention to the potential role of heteroresistance as a contributor to clinical failure. Acknowledgements We would like to thank the Georgia Emerging Infections Program (EIP), Emory’s Investigational Clinical Microbiology Core and Emory Medical Laboratories microbiology staff. Funding L.S.W. is supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under award numbers UL1TR002378 and TL1TR002382. D.S.W. is supported by a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases award. This work was supported by NIH grant Al158080. Transparency declarations None to declare. Supplementary data Table S1, Figures S1 and S2, and Supplementary Methods are available as Supplementary data at JAC Online. References 1 Patel G , Huprikar S, Factor SH et al. Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies . Infect Control Hosp Epidemiol 2008 ; 29 : 1099 – 106 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Band VI , Crispell EK, Napier BA et al. Antibiotic failure mediated by a resistant subpopulation in Enterobacter cloacae . Nat Microbiol 2016 ; 1 : 16053 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Choby JE , Ozturk T, Satola SW et al. Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens . Lancet Infect Dis 2021 ; 21 : 597 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Tamma PD , Aitken SL, Bonomo RA et al. Infectious Diseases Society of America guidance on the treatment of extended-spectrum β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa) . Clin Infect Dis 2021 ; 72 : e169 – 83 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Marshall S , Hujer AM, Rojas LJ et al. Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae? Antimicrob Agents Chemother 2017 ; 61 : e02243-16 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Shields RK , Doi Y. Aztreonam combination therapy: an answer to metallo-β-lactamase-producing Gram-negative bacteria? Clin Infect Dis 2020 ; 71 : 1099 – 101 . Google Scholar Crossref Search ADS PubMed WorldCat 7 CLSI . Performance Standards for Antimicrobial Susceptibility Testing—Thirtieth Edition: M100 . 2020 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 8 EUCAST . Breakpoint Tables for Interpretation of MICs and Zone Diameters, Version 12.0 . 2022 . https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_12.0_Breakpoint_Tables.pdf. 9 Bassetti M , Echols R, Matsunaga Y et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial . Lancet Infect Dis 2021 ; 21 : 226 – 40 . Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
TI - Bacteraemia with an MBL-producing Klebsiella pneumoniae: treatment and the potential role of cefiderocol heteroresistance
JF - Journal of Antimicrobial Chemotherapy
DO - 10.1093/jac/dkac197
DA - 2022-06-21
UR - https://www.deepdyve.com/lp/oxford-university-press/bacteraemia-with-an-mbl-producing-klebsiella-pneumoniae-treatment-and-oxTbkGTMya
SP - 2569
EP - 2571
VL - 77
IS - 9
DP - DeepDyve
ER -