Case Report: Successful Rescue Therapy of Extensively Drug-Resistant Acinetobacter baumannii Osteomyelitis With Cefiderocol.

Cefiderocol is a novel catechol siderophore cephalosporin antibiotic developed to treat resistant gram-negative infections. We describe its successful use as rescue therapy, combined with surgical debridement, to treat a patient with osteomyelitis due to extensively drug-resistant Acinetobacter baumannii. Bacterial whole-genome sequencing identified the strain and antibiotic resistance determinants.

Antimicrobial resistance is a major challenge in modern medicine, and new antibiotics are being developed to combat this problem. One such antibiotic is cefiderocol, a novel siderophore cephalosporin with catechol side chain that leads to bacterial uptake through the iron-transport system [1] and enhanced stability to β-lactamases. Cefiderocol has demonstrated in vitro efficacy against antibiotic-resistant gram-negative organisms [2], including Acinetobacter baumannii [3]. Here we describe successful treatment of osteomyelitis stemming from a polymicrobial infection that included extensively drug-resistant (XDR) A. baumannii. This patient received cefiderocol on a compassionate basis before its recent approval for use in complicated urinary tract infections by the US Food and Drug Administration (FDA) [4].

CASE PRESENTATION

This is a case of a 57-year-old native Tanzanian gentleman, living in the United States, who developed a polymicrobial osteomyelitis that grew XDR A. baumannii. His medical history was significant for type 2 diabetes mellitus and hypertension that were well controlled with diet, metformin, amlodipine, and losartan. Ten days before presentation at our institution, he sustained an open comminuted left tibia and fibula fracture while traveling in his native Tanzania. He underwent external fixation followed by 2 surgical debridements at a local Tanzanian hospital. At that time, he was started on an unknown antibiotic that was presumed to be a tetracycline based on history from the patient.

Upon return to the United States, he presented to our institution due to worsening left leg pain. He was afebrile. Laboratory data were remarkable for leukocytosis (WBC, 12 400 cells/mm3) and elevated inflammatory markers (C-reactive protein [CRP], 4.59 mg/dL; erythrocyte sedimentation rate [ESR], 107 mm/h). X-ray imaging confirmed an open comminuted pilon fracture of the left tibia and fibula. The patient was started on piperacillin/tazobactam and admitted to the hospital (Figure 1).

Figure 1.

Timeline of events. aOutpatient dose gradually increased to 2 g q24H to maintain vancomycin levels of 10–15 mcg/mL. b2.5 mg/kg loading dose then 1.5mg/kg q12H. c8 mg/kg q24H. d2 g q12H. e100 mg loading dose then 50 mg q12H. Abbreviations: AKI, acute kidney injury; Cr, creatinine; ED, emergency department; Pip./Tazo., pipericillin-tazobactam; TMP-SMX, trimethoprim-sulfamethoxazole.

The patient was taken to the operating room on hospital day (HD) 1 for revision of external fixation and surgical debridement. Frank purulence was not encountered, though necrosis along the tendons and muscle bellies of the flexor digitorum longus and flexor hallucis longus muscles was present. He underwent debridement down to the bone at the open fracture site. Tissue cultures from the fracture site grew vancomycin-susceptible Enterococcus faecalis and Corynebacterium striatum, as well as A. baumannii resistant to all routinely tested antibiotics at the Duke Clinical Microbiology Laboratory, including penicillins (ampicillin-sulbactam), cephalosporins (ceftazidime), aminoglycosides (amikacin, gentamicin, tobramycin), fluoroquinolones (ciprofloxacin, levofloxacin), carbapenems (meropenem), tetracyclines (minocycline), and sulfonamides (trimethoprim-sulfamethoxazole).

The patient underwent 3 additional operative debridements on HD3, HD6, and HD13. Intraoperative findings on HD3 and HD6 included stable wound appearance with healthy bleeding tissue. Repeat tissue cultures from HD3 and HD6 again demonstrated growth of E. faecalis, C. striatum, and A. baumannii, while tissue cultures from the final debridement on HD13 were free of bacterial growth. He returned to the operating room on HD15 for vastus lateralis muscle flap placement and definitive internal fixation. The tissue in the wound bed appeared healthy, and samples for tissue culture were not collected.

Antibiotic therapy was complicated by A. baumannii resistance to all tested agents at Duke University, the shipping and processing time associated with sending the bacterial isolate to outside laboratories for further antibiotic testing, and the adverse events associated with the toxic agents initially required to treat this infection. The bacterial isolate was sent to the Mayo Clinic for colistin susceptibility testing and to the Cleveland VA for cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, eravacycline, fosfomycin, meropenem-vaborbactam, plazomicin, and tigecycline testing (Table 1).

Table 1.

Antimicrobial Susceptibility Testing in XDR Acinetobacter baumannii

	Antibiotic Susceptibility Testing
Antibiotic	Value	Unit (Method)	Interpretationa
Amikacin	>32	mcg/mL (MIC)	Resistant
Amoxicillin + clavulanate	>16/8	mcg/mL (MIC)	Resistant
Ampicillin	>16	mcg/mL (MIC)	Resistant
Ampicillin + sulbactam	>16/8	mcg/mL (MIC)	Resistant
Aztreonam	>16	mcg/mL (MIC)	Resistant
Cefazolin	>16	mcg/mL (MIC)	Resistant
Cefepime	>16	mcg/mL (MIC)	Resistant
Cefiderocol	23	mm (ZOI)	Susceptible
Ceftazidime	>16	mcg/mL (MIC)	Resistant
Ceftazidime + avibactam	15	mm (ZOI)	Resistant
Ceftolozane + tazobactam	10	mm (ZOI)	Resistant
Ceftriaxone	>32	mcg/mL (MIC)	Resistant
Cefuroxime	>16	mcg/mL (MIC)	Resistant
Ciprofloxacin	>2	mcg/mL (MIC)	Resistant
Colistin	≤2	mcg/mL (MIC)	Susceptible
Eravacycline	15	mm (ZOI)	Resistantb
Ertapenem	6	mm (ZOI)	Resistant
Fosfomycin	17	mm (ZOI)	Susceptible
Gentamicin	>8	mcg/mL (MIC)	Resistant
Imipenem	6	mm (ZOI)	Resistant
Levofloxacin	>4	mcg/mL (MIC)	Resistant
Meropenem	>8	mcg/mL (MIC)	Resistant
Minocycline	14	mm (ZOI)	Intermediate
Meropenem + vaborbactam	6	mm (ZOI)	Resistant
Nitrofurantoin	>64	mcg/mL (MIC)	Resistant
Piperacillin	6	mm (ZOI)	Resistant
Tetracycline	>8	mcg/mL (MIC)	Resistant
Tigecycline	6	mm (ZOI)	Resistantb
Tobramycin	>8	mcg/mL (MIC)	Resistant
Trimethoprim + sulfamethoxazole	>2/38	mcg/mL (MIC)	Resistant

Abbreviations: MIC, minimum inhibitory concentration; XDR, extensively drug-resistant; ZOI, zone of inhibition.

aThese interpretations are based on Clinical and Laboratory Standards Institute standard breakpoints unless otherwise specified.

bNo Clinical and Laboratory Standards Institute breakpoints are currently published for these agents. Interpretation was based on Food and Drug Administration identified susceptibility test interpretive criteria for Enterobacteriaceae.

Before the receipt of outside laboratory antibiotic susceptibility data, the patient was managed primarily with a combination of intravenous (IV) vancomycin, IV polymyxin B, and IV minocycline (Figure 1). On HD5, the patient developed acute kidney injury (AKI). His serum creatinine rose from a baseline of 1.3 mg/dL to a maximum of 4.3 mg/dL on HD7. Therefore, minocycline and polymyxin B were discontinued and replaced with tigecycline and meropenem. Despite intensive antibiotic therapy, cultures from the fifth surgical debridement on HD6 continued to grow XDR A. baumannii.

When the complete susceptibility profile of A. baumannii was available on HD7, it was found to only be susceptible to fosfomycin, colistin, and cefiderocol. Compassionate use cefiderocol was pursued under an emergency Investigational New Drug application to the US FDA, approved by the drug manufacturer (Shionogi), and started on HD7. Daptomycin was continued for treatment of E. faecalis and C. striatum. By HD12, the patient’s kidney function had improved. He was receiving cefiderocol (2 g q8H) infused over 3 hours. After 6 days of cefiderocol therapy, the patient’s sixth and final debridement on HD13 revealed sterile tissue cultures, the first indication of a positive microbiological response.

The patient’s renal function returned to baseline and, aside from an episode of rhabdomyolysis secondary to daptomycin, he recovered smoothly and was discharged on HD26 with vancomycin IV and cefiderocol through a peripherally inserted central catheter. The patient reported no drug-related side effects or infusion site reactions. Weekly monitoring of laboratory studies showed no leukopenia, leukocytosis, AKI, or liver injury. He improved by all measures. He had no evidence of active infection on physical exam. Inflammatory markers normalized, with ESR 12 mm/h and CRP 0.29 mg/dL. Radiographic studies after 102 days of cefiderocol therapy demonstrated interval fracture healing with progressive sclerosis and callus formation at the fracture site. Antibiotics were discontinued 116 days after he was initially admitted to the hospital. His course of cefiderocol totaled 109 days. Follow-up clinic visits 21, 65, and 128 days after cessation of antibiotics demonstrated no evidence of persistent or relapsed infection.

Whole-genome sequencing (WGS) was performed on the XDR A. baumannii. The genomic library was prepared with the Illumina NexteraXT kit and sequenced with the Illumina NextSeq 550 platform. Assembly and annotation of sequencing reads were performed with PATRIC [5]. Identification of antibiotic resistance genes was confirmed using ResFinder [6]. Multilocus sequence types (MLSTs) were 195 (Oxford scheme) and 2 (Pasteur scheme). Twelve putative antibiotic resistance genes were identified (Table 2). Of note, this strain carried OXA-23, an acquired class D β-lactamase associated with carbapenem resistance [7, 8]. The presence of OXA-66 β-lactamase could also play a role in carbapenem resistance, as it has been associated with nonsusceptibility to imipenem [9-11]. The presence of armA is associated with resistance to aminoglycosides. Gene tetB encodes an acquired efflux pump conferring resistance to minocycline. No mutations in the fluoroquinolone resistance genes gyrA, parC, or parE were detected. No mutations in endogenous porins or efflux pumps known to influence resistance were detected.

Table 2.

Antibiotic Resistance Determinants in XDR Acinetobacter baumannii; Antibiotic Resistance Genes Were Detected by Whole-Genome Sequencing

Gene	Resistance Mechanism	Conferred Resistance	References
aph3’’-Ib	Enzymatic antibiotic inactivation	Aminoglycosides	[20–22]
aph3’-Ia	Enzymatic antibiotic inactivation	Aminoglycosides	[20, 22]
aph6-Id	Enzymatic antibiotic inactivation	Aminoglycosides	[20–22]
armA	Antibiotic target (16S ribosome) methylation	Aminoglycosides	[20–22]
blaADC-73	β-lactamase	β-lactams	[20, 23, 24]
blaOXA-23	β-lactamase	β-lactams, including carbapenems	[7, 8, 20–23]
blaOXA-66	β-lactamase	β-lactams, including carbapenems	[9–11, 20–22]
blaTEM-1D	β-lactamase	β-lactams	[20–22, 25]
sul2	Antibiotic target (di-hydro-pteroate synthase) alteration	Sulfonamides	[20–22]
mphE	Enzymatic antibiotic inactivation	Macrolides	[20, 22, 26]
msrE	Antibiotic target (ribosome) protection	Macrolides	[20, 22, 26]
tetB	Antibiotic efflux pump	Tetracyclines	[20–22]

Abbreviation: XDR, extensively drug-resistant.

Discussion

To our knowledge, this case is the first to document use of cefiderocol as rescue treatment adjuvant to surgical debridement for osteomyelitis containing XDR A. baumannii. Cefiderocol was successfully employed where no other commercially available drug options existed. A similar case report demonstrated successful use of cefiderocol to treat chronic osteomyelitis due to XDR Pseudomonas aeruginosa and extended-spectrum β-lactamase-producing Klebsiella pneumoniae [12]; however, our case is promising in light of recent results from the CREDIBLE-CR study, which investigated the use of cefiderocol vs best available therapy to treat carbapenem-resistant gram-negative infections [13]. In patients with A. baumannii infections, CREDIBLE-CR demonstrated a decreased rate of clinical cure and an increased rate of clinical failure in patients treated with cefiderocol.

The success of cefiderocol likely stemmed from the unique structure of the siderophore cephalosporin with a catechol side chain, which confers stability against hydrolytic enzymes such as OXA β-lactamases [14] and allows for enhanced cellular uptake [1]. This mechanism of uptake via the bacterial iron-transport system may play a role in cefiderocol’s efficacy against biofilm-associated infections such as osteomyelitis. Iron is crucial for biofilm formation, and siderophore production is upregulated in biofilms [15]. Furthermore, both uptake and in vitro activity of cefiderocol increase when bacterial iron acquisition systems are upregulated [1]. Thus cefiderocol may be particularly useful against biofilm-forming bacteria by capitalizing on their enhanced iron uptake.

Successful reports of cefiderocol rescue therapy in resistant gram-negative bacteremia secondary to pneumonia [3] and endocarditis [16] have been described. This case lends support to the idea that cefiderocol can penetrate bone tissue in sufficient concentrations when administered as 2 g 3 times daily. The success of this dosing schedule is consistent with other cephalosporins, as their bactericidal activity is linked to the proportion of time the plasma concentration exceeds the MIC [17].

This case also highlights the improved side effect profile of cefiderocol relative to alternative therapies for XDR A. baumannii, such as polymyxins, particularly regarding nephrotoxicity. CREDIBLE-CR reported lower rates of drug-related AKI in patients receiving cefiderocol relative to best available therapy [13], adding to previous research demonstrating its safety [18, 19]. In addition, this case and multiple additional reports have described the safe and successful use of cefiderocol to treat serious infections caused by gram-negative bacteria [3, 12, 16].

Conclusions

This case illustrates the successful treatment of osteomyelitis caused in part by XDR A. baumanni with surgical debridement and cefiderocol when no viable alternative antibiotics existed. Although more clinical and pharmacokinetic data are needed to understand the degree to which cefiderocol can penetrate bone and treat osteomyelitis, this case demonstrates that cefiderocol can be considered as rescue therapy in conjunction with surgical debridement for highly antibiotic-resistant gram-negative bacterial osteomyelitis.