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Cefiderocol treatment of Pseudomonas aeruginosa and extensively drug-resistant Acinetobacter baumannii retained spinal hardware infection causing reversible acute interstitial nephritis

Recto: Cefiderocol causing acute interstitial nephritis
  • Kimberly Cipko
    Correspondence
    Corresponding author: Kimberly Cipko, Department of Infectious Diseases, Immunology and Sexual Health, St George Hospital, 2 South Street, Kogarah, New South Wales 2217, Australia. Tel: +61 2 9113 2955. Fax: +61 2 9113 3891.
    Affiliations
    Department of Infectious Diseases, Immunology and Sexual Health, St George Hospital, Sydney, New South Wales, Australia

    Graduate School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia
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  • Alice Kizny Gordon
    Affiliations
    Department of Microbiology, New South Wales Health Pathology, St George Hospital, New South Wales, Australia

    St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
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  • Suman Adhikari
    Affiliations
    St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia

    Department of Pharmacy, St George Hospital, Sydney, New South Wales, Australia
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  • Pamela Konecny
    Affiliations
    Department of Infectious Diseases, Immunology and Sexual Health, St George Hospital, Sydney, New South Wales, Australia

    St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
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Open AccessPublished:June 19, 2021DOI:https://doi.org/10.1016/j.ijid.2021.06.035

      Highlights

      • This article reports successful cefiderocol salvage of infected irremovable lumbar fusion hardware.
      • The patient had a Pseudomonas and extensively drug-resistant Acinetobacter baumannii (XDRAB) spinal infection.
      • The XDRAB was susceptible to cefiderocol.
      • Cefiderocol-associated acute interstitial nephritis was reversible.
      • The novel siderophore action of cefiderocol has potential for enhanced biofilm activity.

      Abstract

      Infections with extensively drug-resistant Acinetobacter baumannii (XDRAB) have limited therapeutic options. We report successful salvage treatment of XDRAB and Pseudomonas aeruginosa-infected retained spinal hardware with cefiderocol, despite the development of reversible acute interstitial nephritis after 32 days of treatment.

      KEYWORDS

      1. Introduction

      Limited treatment options exist for extensively drug-resistant Acinetobacter baumannii (XDRAB) (
      • Theuretzbacher U
      • Bush K
      • Harbarth S
      • Paul M
      • Rex JH
      • Tacconelli E
      • et al.
      Critical analysis of antibacterial agents in clinical development.
      ). Cefiderocol is a novel siderophore cephalosporin able to utilize bacterial iron transport mechanisms, in addition to porin channels, to enter cells and inhibit cell wall synthesis (
      • Wu JY
      • Srinivas P
      • Pogue JM.
      Cefiderocol: a novel agent for the management of multidrug-resistant Gram-negative organisms.
      ). It is a poor efflux pump substrate and demonstrates enhanced stability against hydrolysis by amp-C beta-lactamases, extended-spectrum beta-lactamases (ESBL), and most carbapenemases (
      • Wu JY
      • Srinivas P
      • Pogue JM.
      Cefiderocol: a novel agent for the management of multidrug-resistant Gram-negative organisms.
      ), resulting in activity against carbapenem-resistant Enterobacterales (CRE) and multidrug-resistant (MDR) Pseudomonas and Acinetobacter species. Evidence is emerging for its potential role in treating biofilms, where bacterial siderophore production is upregulated (
      • Pybus C
      • Felder-Scott C
      • Obuekwe V
      • Greenberg D.
      Cefiderocol retains anti-biofilm activity in multi-drug resistant Gram-negative pathogens.
      ).

      2. Case report

      An 81-year-old female patient underwent an elective stereotactic L3–S1 laminectomy, decompression, and pedicle screw fixation with posterior lumbar (L5/S1) interbody fusion (PLIF) to treat worsening neuropathic back pain, in a tertiary hospital in Sydney, Australia in January 2020. Her past medical history included asthma, hypertension, and osteoporosis. The index surgery on admission (day 0) was complicated by anterior displacement of the PLIF hardware (NuVasive, nuvasive.com/procedures/spine/mas-plif) into the retroperitoneal space, retrieved surgically the following day, when she underwent an anterior L5–S1 discectomy and interbody allograft of demineralised bone matrix (Grafton) insertion. The patient had no risk of exposure to, or history of colonization with multi-resistant organisms, although CRE screening was not performed. Cefazolin perioperative prophylaxis was used.
      On days 10–13, the patient received empiric intravenous (IV) ceftriaxone and vancomycin for a superficial, non-discharging wound infection, without microbiological sampling. On day 22, increasing lumbar pain, purulent wound discharge and dehiscence, a temperature of 37.8°C, and C-reactive protein (CRP) rising to 66 mg/l, from 10 mg/l on day 10 (normal <5 mg/l), prompted surgical debridement, infectious diseases consultation, and the initiation of empiric piperacillin–tazobactam and vancomycin (Figure 1). A heavy growth of both pan-susceptible Pseudomonas aeruginosa and XDRAB, phenotypically susceptible only to amikacin and polymyxins using the calibrated dichotomous sensitivity (CDS) method (

      Bell SM, Pham JN, Rafferty DL, Allerton JK, James PM. Antibiotic susceptibility testing by the CDS method. A manual for medical and veterinary laboratories, 9th Ed. Kogarah (Australia): The CDS Reference Laboratory; 2018. http://cdstest.net/manual. [accessed 20 May 2021]

      ), were isolated from frank pus deep to fascia around the metalware. The XDRAB isolate was referred to the reference laboratory at the Institute of Clinical Pathology and Medical Research (ICPMR, Westmead, Sydney) for further phenotypic, molecular, and genomic susceptibility testing. The minimum inhibitory concentrations (MIC) for this isolate, determined prior to the initiation of cefiderocol treatment, are reported in Table 1. Multiplex PCR testing for plasmid-mediated carbapenemases was positive for blaOXA-23 and negative for blaIMP, blaNDM, blaKPC, blaOXA-48, and blaVIM. Whole genome sequencing identified the XDRAB isolate as sequence type 2, and confirmed carriage of a plasmid-bound blaOXA-23, as well as other resistance genes including the following: blaOXA-66 (chromosomal); aacA4, aadA1, strB (aminoglycosides); sul2 (sulfur); and tet (tetracycline).
      Figure 1
      Figure 1Serum creatinine and absolute eosinophil count in relation to antibiotic use over time.
      Table 1Extensively drug-resistant Acinetobacter baumannii MICs, interpretation, and method used
      AntibioticMIC (μg/ml)Interpretive guidelinesMethod
      Amikacin≤16Susceptible (CDS
      Calibrated dichotomous sensitivity test. Bell SM, Pham JN, Rafferty DL, Allerton JK, James PM. Antibiotic susceptibility testing by the CDS method. A manual for medical and veterinary laboratories. Ninth edition. Kogarah, Australia: The CDS Reference Laboratory; 2018. http://cdstest.net/manual (accessed May 20, 2021).
      )
      Disc diffusion
      Aztreonam>84No guidelines availableBroth microdilution
      Broth microdilution was performed in the reference laboratory at the Institute of Clinical Pathology and Medical Research, Westmead Hospital.
      Aztreonam–avibactam>64/4No guidelines availableBroth microdilution
      Cefepime>2Resistant (CDS)Disc diffusion
      Cefiderocol0.5Susceptible (CLSI
      Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. 31st edition. CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2021.
      )
      Broth microdilution
      Iron-depleted cation-adjusted Mueller–Hinton broth prepared according to CLSI recommendations was used to perform broth microdilution in the reference laboratory at the Institute of Clinical Pathology and Medical Research, Westmead Hospital.
      Ceftazidime–avibactam25Resistant (EUCAST
      The European Committee on Antimicrobial Susceptibility Testing. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters, version 10.0, 2020. https://eucast.org/clinical_breakpoints (accessed May 20 2021).
      )
      Gradient diffusion
      Ceftriaxone>1Resistant (CDS)Disc diffusion
      Chloramphenicol>8Resistant (CDS)Disc diffusion
      Ciprofloxacin>1Resistant (CDS)Disc diffusion
      Colistin1Susceptible (EUCAST)Broth microdilution
      Eravacycline1No guidelines availableBroth microdilution
      Fosfomycin>32Resistant (CDS)Disc diffusion
      Gentamicin>2Resistant (CDS)Disc diffusion
      Imipenem>32Resistant (EUCAST)Broth microdilution
      Imipenem–relebactam>32/4Resistant (EUCAST)Broth microdilution
      Meropenem>32Resistant (EUCAST)Broth microdilution
      Meropenem–vaborbactam>32/8No guidelines availableBroth microdilution
      Piperacillin–tazobactam>16/2Resistant (CDS)Disc diffusion
      Polymyxin B1No guidelines availableBroth microdilution
      Tigecycline4No guidelines availableBroth microdilution
      Trimethoprim–sulfamethoxazole>1/19Resistant (CDS)Disc diffusion
      MIC, minimum inhibitory concentration.
      a Calibrated dichotomous sensitivity test. Bell SM, Pham JN, Rafferty DL, Allerton JK, James PM. Antibiotic susceptibility testing by the CDS method. A manual for medical and veterinary laboratories. Ninth edition. Kogarah, Australia: The CDS Reference Laboratory; 2018. http://cdstest.net/manual (accessed May 20, 2021).
      b Broth microdilution was performed in the reference laboratory at the Institute of Clinical Pathology and Medical Research, Westmead Hospital.
      c Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. 31st edition. CLSI supplement M100. Wayne, PA: Clinical and Laboratory Standards Institute; 2021.
      d Iron-depleted cation-adjusted Mueller–Hinton broth prepared according to CLSI recommendations was used to perform broth microdilution in the reference laboratory at the Institute of Clinical Pathology and Medical Research, Westmead Hospital.
      e The European Committee on Antimicrobial Susceptibility Testing. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters, version 10.0, 2020. https://eucast.org/clinical_breakpoints (accessed May 20 2021).
      The patient's hardware was irremovable due to spinal instability. Pan-sensitive P. aeruginosa and XDRAB continued to be isolated from deep wound swabs during 19 days of piperacillin–tazobactam monotherapy. Aminoglycoside therapy was contraindicated due to chronic hearing impairment and tinnitus. On day 41, piperacillin–tazobactam was switched to colistin 300 mg IV loading dose, then 110 mg IV twice daily, and tigecycline 100 mg IV loading dose, then 50 mg IV twice daily. Within 48 hours of colistin treatment (day 43), the patient had developed colistin-induced neurotoxicity, manifesting as vertigo, paraesthesia of the lower face, dysarthria, and poor balance, and nephrotoxicity with creatinine rising from a baseline of 50 μmol/l to 170 μmol/l (normal 45–90 μmol/l) (Figure 1). Colistin was ceased and piperacillin–tazobactam was re-commenced. The patient experienced side-effects from tigecycline including nausea, anorexia, and reflux, minimally responsive to antiemetics and a proton pump inhibitor, necessitating cessation 6 days later (day 49).
      Cefiderocol was supplied by Shionogi Co., Ltd (Osaka, Japan) and imported under the Australian Therapeutic Goods Administration Special Access Scheme (TGA, https://sas.tga.gov.au/). Cefiderocol monotherapy was commenced on day 50 at a renally adjusted dose of 1.5 g IV every 8 hours. This dose was up-titrated to 2 g IV every 8 hours as the patient's renal function normalized.
      The patient improved clinically, but after 24 days of cefiderocol, the patient developed another episode of acute kidney injury (AKI) (creatinine increased from 84 μmol/l to 173 μmol/l), associated with peripheral blood eosinophilia of 0.60 × 10−9/l (normal 0.04–0.44 × 10−9/l) (Figure 1) and accelerated hypertension to 195/80 mmHg. No concurrent nephrotoxic medications had been prescribed. Mid-stream urine microscopy was normal, with no eosinophils detected. Nephrologist review established a diagnosis of probable acute interstitial nephritis (AIN) secondary to cefiderocol, scoring 6 on the Naranjo probability scale (
      • Naranjo CA
      • Busto U
      • Sellers EM
      • Sandor P
      • Ruiz I
      • Roberts EA
      • et al.
      A method for estimating the probability of adverse drug reactions.
      ). A renal biopsy was not pursued given the patient's frailty and plateauing renal function. Cefiderocol was ceased after 32 days of therapy (day 81), at which time the patient's wound had healed, pain improved, and CRP normalized. Peripheral eosinophilia resolved within 1 week, and creatinine returned to baseline 16 days after discontinuing cefiderocol (Figure 1).
      The patient did not receive further XDRAB-directed therapy due to a lack of available options (Table 1). Antibiotic therapy for P. aeruginosa was continued with oral ciprofloxacin. The patient was discharged home on day 85. Outpatient review on day 94 demonstrated clinical recovery and normal CRP, so ciprofloxacin was ceased (10 weeks of anti-pseudomonal treatment), with a plan for ongoing close observation. The patient has remained well, at pre-morbid status, with healed spinal wound, normal renal function, and normal CRP at 15 months.

      3. Discussion

      This report describes successful cefiderocol salvage treatment of a complicated spinal infection with XDRAB and pan-sensitive P. aeruginosa, involving irremovable metallic hardware. In the only other reported case of XDRAB deep spinal wound hardware infection, involving a 64-year-old polytrauma patient, it was possible to remove the hardware (
      • Zingg S
      • Nicoletti GJ
      • Kuster S
      • Junker M
      • Widmer A
      • Egli A
      • et al.
      Cefiderocol for extensively drug-resistant Gram-negative bacterial Infections: real-world experience from a case series and review of the literature.
      ). Cefiderocol-associated AIN has not been reported previously, and this resolved on discontinuation. This serious adverse drug reaction was reported to Shionogi & Co., Ltd and to the TGA. On review at 15 months, the patient demonstrated a durable response to treatment, despite discontinuation of XDRAB-specific therapy at 32 days.
      Cefiderocol is an emerging option for treating MDR gram-negative infections (
      • Wu JY
      • Srinivas P
      • Pogue JM.
      Cefiderocol: a novel agent for the management of multidrug-resistant Gram-negative organisms.
      ). In the CREDIBLE-CR study, the efficacy and safety profiles were similar in cefiderocol-treated carbapenem-resistant gram-negative nosocomial pneumonia, sepsis, bloodstream infections, and complicated urinary tract infections compared to ‘best available treatment’, although there were more deaths in cefiderocol-treated A. baumannii infections (
      • Bassetti M
      • Echols R
      • Matsunaga Y
      • Ariyasu M
      • Doi Y
      • Ferrer R
      • 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.
      ). There is limited real-world clinical experience using cefiderocol for complex infections beyond the urinary or respiratory tract. A comprehensive literature search identified four other cases of treatment of XDRAB acute osteomyelitis (
      • Dagher M
      • Ruffin F
      • Marshall S
      • Taracila M
      • Bonomo RA
      • Reilly R
      • et al.
      Case report: Successful rescue therapy of extensively drug-resistant Acinetobacter baumannii osteomyelitis with cefiderocol.
      ;
      • Zingg S
      • Nicoletti GJ
      • Kuster S
      • Junker M
      • Widmer A
      • Egli A
      • et al.
      Cefiderocol for extensively drug-resistant Gram-negative bacterial Infections: real-world experience from a case series and review of the literature.
      ). Given its potential for biofilm activity (
      • Pybus C
      • Felder-Scott C
      • Obuekwe V
      • Greenberg D.
      Cefiderocol retains anti-biofilm activity in multi-drug resistant Gram-negative pathogens.
      ), good bone penetration of cephalosporins, and the low rate of adverse effects (
      • Bassetti M
      • Echols R
      • Matsunaga Y
      • Ariyasu M
      • Doi Y
      • Ferrer R
      • 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.
      ,
      • Wu JY
      • Srinivas P
      • Pogue JM.
      Cefiderocol: a novel agent for the management of multidrug-resistant Gram-negative organisms.
      ), cefiderocol is a promising agent for use in orthopaedic hardware-associated infections, particularly where alternative antibiotics are precluded.
      Cefiderocol is generally well tolerated, with fewer side effects than existing alternative treatments for XDRAB. Gastrointestinal side effects are the most common (
      • Theuretzbacher U
      • Bush K
      • Harbarth S
      • Paul M
      • Rex JH
      • Tacconelli E
      • et al.
      Critical analysis of antibacterial agents in clinical development.
      ;
      • Wu JY
      • Srinivas P
      • Pogue JM.
      Cefiderocol: a novel agent for the management of multidrug-resistant Gram-negative organisms.
      ), and neutropenia has been reported with prolonged cefiderocol treatment (
      • Alamarat ZI
      • Babic J
      • Tran TT
      • Wootton SH
      • Dinh AQ
      • Miller WR
      • et al.
      Long-term compassionate use of cefiderocol to treat chronic osteomyelitis caused by extensively drug-resistant Pseudomonas aeruginosa and extended-spectrum-β-lactamase-producing Klebsiella pneumoniae in a pediatric patient.
      ). AIN attributable to cefiderocol has not been reported in any of the previously published clinical cases, nor was it reported in the CREDIBLE-CR study (
      • Alamarat ZI
      • Babic J
      • Tran TT
      • Wootton SH
      • Dinh AQ
      • Miller WR
      • et al.
      Long-term compassionate use of cefiderocol to treat chronic osteomyelitis caused by extensively drug-resistant Pseudomonas aeruginosa and extended-spectrum-β-lactamase-producing Klebsiella pneumoniae in a pediatric patient.
      ;
      • Bassetti M
      • Echols R
      • Matsunaga Y
      • Ariyasu M
      • Doi Y
      • Ferrer R
      • 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.
      ;
      • Contreras DA
      • Fitzwater SP
      • Nanayakkara DD
      • Schaenmann J
      • Aldrovandi GM
      • Garner OB
      • et al.
      Coinfections of two strains of NDM-1- and OXA-232-coproducing Klebsiella pneumoniae in a kidney transplant patient.
      ;
      • Dagher M
      • Ruffin F
      • Marshall S
      • Taracila M
      • Bonomo RA
      • Reilly R
      • et al.
      Case report: Successful rescue therapy of extensively drug-resistant Acinetobacter baumannii osteomyelitis with cefiderocol.
      ;
      • Edgeworth JD
      • Merante D
      • Patel S
      • Young C
      • Jones P
      • Vithlani S
      • et al.
      Compassionate use of cefiderocol as adjunctive treatment of native aortic valve endocarditis due to extremely drug-resistant Pseudomonas aeruginosa.
      ;
      • Gainey AB
      • Burch AK
      • Brownstein MJ
      • Brown DE
      • Fackler J
      • Horne B
      • et al.
      Combining bacteriophages with cefiderocol and meropenem/vaborbactam to treat a pan-drug resistant Achromobacter species infection in a pediatric cystic fibrosis patient.
      ;
      • Kufel WD
      • Steele JM
      • Riddell SW
      • Jones Z
      • Shakeraneh P
      • Endy TP.
      Cefiderocol for treatment of an empyema due to extensively drug-resistant Pseudomonas aeruginosa: Clinical observations and susceptibility testing considerations.
      ;
      • Siméon S
      • Dortet L
      • Bouchand F
      • Roux AL
      • Bonnin RA
      • Duran C
      • et al.
      Compassionate use of cefiderocol to treat a case of prosthetic joint infection due to extensively drug-resistant Enterobacter hormaechei.
      ;
      • Trecarichi EM
      • Quirino A
      • Scaglione V
      • Longhini F
      • Garofalo E
      • Bruni A
      • et al.
      IMAGES Group. Successful treatment with cefiderocol for compassionate use in a critically ill patient with XDR Acinetobacter baumannii and KPC-producing Klebsiella pneumoniae: a case report.
      ;
      • Zingg S
      • Nicoletti GJ
      • Kuster S
      • Junker M
      • Widmer A
      • Egli A
      • et al.
      Cefiderocol for extensively drug-resistant Gram-negative bacterial Infections: real-world experience from a case series and review of the literature.
      ).
      In conclusion, we present the complicated case of an 81-year-old female patient with a deep spinal wound infection involving non-removable hardware caused by XDRAB and pan-sensitive P. aeruginosa, successfully salvaged with cefiderocol treatment. Cefiderocol-associated AIN was reversible. Further clinical data are needed to inform the efficacy and safety profile of cefiderocol in complex MDR gram-negative infections.

      Declaration of Competing Interest

      No conflicts of interest to declare.

      Acknowledgements

      The authors would like to thank Shionogi & Co. Ltd, for providing compassionate access to cefiderocol for use in Australia; Dr Robert Stevens, NSW Health Pathology, St George Hospital, Sydney for his input regarding susceptibility testing of the XDRAB isolate; and the Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, for performing extended antimicrobial susceptibility testing.

      Funding source

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Ethical approval

      The patient provided written informed consent for publication of this case report in print and electronic form.

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