Postsurgical infection with carbapenemase-producing Enterobacterales in a 45-year-old woman

Key points

• Gram-negative bacteria frequently acquire resistance to antibiotics, and infections from multidrug-resistant gram-negative bacteria are increasing.

• Carbapenemase-producing Enterobacterales (CPE) are gram-negative bacteria resistant to carbapenems, antibiotics that are historically drugs of last resort in treating multidrug-resistant infections.

• In addition to carbapenems, CPE are often resistant to many other antibiotic classes, making infections with these organisms challenging to treat.

• Select novel β-lactam antibiotics are now available to treat infections with CPE, but access for timely initiation and susceptibility testing remains challenging.

A 45-year-old previously healthy woman was admitted to our hospital for surgical management of a nonhealing traumatic upper extremity injury. Approximately 6 months earlier, she sustained a motor vehicle collision in Nigeria, resulting in open fractures to her right distal humerus, radius, and ulna. At the time of her injury, she underwent irrigation, débridement, and external fixation of her fractures. She developed a surgical-site infection 2 months later while still in Nigeria, requiring irrigation, débridement, and internal fixation of her distal humerus. Her radius and ulna remained in nonunion, and her right forearm was casted for several months after removal of the external fixation. She received several courses of antibiotic therapy, the details of which were not available.

Shortly after she moved to Canada, the patient presented to the emergency department at her local hospital and was subsequently referred to the orthopedic surgery clinic at our hospital. On examination, she was afebrile, with heart rate of 84 beats/min and blood pressure of 121/68 mm Hg. Her right forearm had a varus deformity and her elbow was fixed in flexion. An extensive surgical incision extended from her right antecubital fossa to distal forearm, with a few small nondraining regions of dehiscence. She had pain, stiffness, and decreased range of motion. Laboratory investigations demonstrated normal leukocyte count, but C-reactive protein of 96.0 (normal < 5.0) mg/L. Radiographs showed nonunion of the distal humerus fracture with failure of the internal fixation, and nonunion of the radius and ulna fractures. The following week, the patient was electively admitted to our hospital and underwent irrigation, débridement, and open reduction and internal fixation of the distal humerus, radius, and ulna. Intraoperatively, purulent fluid, bone necrosis, and destruction of the elbow joint were noted. The orthopedic surgery service started intravenous cefazolin 2 g every 8 hours postoperatively.

Operative cultures returned positive for Klebsiella pneumoniae. Our infectious diseases service was consulted to guide antibiotic management. We changed cefazolin to intravenous piperacillin–tazobactam 4.5 g every 6 hours. Antibiotic susceptibility testing demonstrated resistance to all routinely tested antibiotics. Rapid testing for carbapenemase production was positive for New Delhi metallo-β-lactamase (NDM). We started intravenous ceftazidime–avibactam 2.5 g every 8 hours and intravenous aztreonam 2 g every 8 hours within 6 hours of NDM detection (Figure 1). We obtained emergency telephone approval from Health Canada’s Special Access Program (SAP) to access both medications, and had existing stock in our pharmacy that could be started expeditiously while awaiting shipment from the manufacturer.

Figure 1:

Timeline of microbiologic investigations and antibiotic treatment after surgery, in a 45-year-old woman with postsurgical infection with carbapenemase-producing Enterobacterales. Note: MALDI-TOF = matrix-assisted laser desorption/ionization-time of flight.

The patient completed 6 weeks of treatment. At follow-up 1 year after surgery, she had reduced pain, a well-healed incision, and normalization of C-reactive protein to 3.6 mg/L. However, she had ongoing stiffness and decreased range of motion.

Discussion

Gram-negative bacteria are major causes of infection worldwide. The order Enterobacterales comprises the majority of clinically significant gram-negative bacteria, including Escherichia coli, Klebsiella species, and Enterobacter species. Gram-negative bacteria can develop antibiotic resistance through numerous mechanisms. Resistance to β-lactam antibiotics frequently occurs through β-lactamases, enzymes that hydrolyze the β-lactam ring. Although numerous β-lactams have been developed to circumvent these processes, new β-lactamases have consistently emerged, conferring resistance to these agents. Extended-spectrum β-lactamases, which confer resistance to most β-lactams — including penicillins, β-lactam and β-lactamase inhibitor combinations (e.g., piperacillin–tazobactam), first-to fourth-generation cephalosporins, and aztreonam — are commonly encountered in Canada.¹

Carbapenems have historically been the β-lactam antibiotics of last resort in treating multidrug-resistant gram-negative infections. Carbapenemases are a type of β-lactamase that can inactivate carbepenems. Carbapenemase-producing Enterobacterales (CPE) were first identified in Canada in 2007, and incidence has progressively increased, consistent with global trends.^2,3 In Canada, CPE were historically imported from countries of endemicity, particularly with out-of-country health care exposure. However, local acquisition and transmission in health care settings is increasing.⁴ Appropriate infection prevention and control measures are therefore critical; patients with CPE colonization require contact precautions in hospital.⁵ Mortality of 20% to 50% has been reported in patients infected with CPE.⁶

Carbapenemases are typically classified using the Ambler molecular classification scheme for β-lactamases (Appendix 1, available at www.cmaj.ca/lookup/doi/10.1503/cmaj.251218/tab-related-content). Importantly, this classification is used by microbiology laboratories to report carbapenemase detection and informs antibiotic selection. The class A K. pneumoniae carbapenemase and the class B NDM are most common in Canada, comprising 34.9% and 34.7% of cases in 2023, respectively, followed by the class D OXA-48 and OXA-48-like carbapenemases (20.7%).² Class C β-lactamases cannot hydrolyze carbapenems, and thus carbapenems are generally effective for organisms that carry them (Appendix 1).

Conventional antibiotics are typically inadequate for treating infections with CPE, and CPE are frequently resistant to non-β-lactam antibiotic classes as well. New β-lactam antibiotics have been developed for CPE and incorporated into guidance from the Infectious Diseases Society of America (Table 1).⁷ Three are combinations of existing β-lactams with novel β-lactamase inhibitors preventing hydrolysis by carbapenemases: ceftazidime–avibactam, imipenem–cilastatin–relebactam, and meropenem–vaborbactam. Importantly, there are differences in expected activity across carbapenemase classes (summarized in Table 1). Another new β-lactam is cefiderocol, which is expected to be effective against all carbapenemases, although it should be preferentially reserved for class B carbapenemases.⁷ Lastly, aztreonam–avibactam, a novel β-lactam and β-lactamase inhibitor combination, is anticipated but has not yet been incorporated into Infectious Diseases Society of America guidance and has not yet been made available in Canada by its manufacturer.

Table 1:

Summary of new β-lactam antibiotics currently accessible in Canada

Antibiotic	Mechanism	Expected activity against carbapenemases			Access
		Class A	Class B	Class D
Ceftolozane–tazobactam*	Combination of novel β-lactam and established β-lactamase inhibitor	No	No	No	Through standard hospital channels
Ceftazidime–avibactam	Combination of established β-lactam and novel β-lactamase inhibitor	Yes	In combination with aztreonam†	Yes	Application to SAP
Imipenem–cilastatin–relebactam	Combination of established β-lactam and novel β-lactamase inhibitor	Yes	No	No	Through standard hospital channels
Meropenem–vaborbactam	Combination of established β-lactam and novel β-lactamase inhibitor	Yes	No	No	Through standard hospital channels
Cefiderocol	Siderophore cephalosporin — leverages bacterial iron transport system to enter bacteria and inhibit cell wall synthesis	Yes (less preferred)‡	Yes	Yes (less preferred)‡	Application to SAP

Note: SAP = Special Access Program.

^*Ceftolozane–tazobactam has limited activity against carbapenemase-producing Enterobacterales and is primarily used for infection with multidrug-resistant Pseudomonas aeruginosa that does not produce carbapenemases.

^†Combination ceftazidime–avibactam and aztreonam is recommended for class B carbapenemases, as aztreonam is resistant to hydrolysis by class B carbapenemases, whereas ceftazidime–avibactam protects against other β-lactamases that are frequently co-produced. Aztreonam requires application to Health Canada’s SAP as well.

^‡Although expected to have activity against class A and class D carbapenemases, cefiderocol is less preferred owing to limited clinical evidence, and to reserve it for class B carbapenemases.

In patients with suspected CPE infection, prompt initiation of appropriate antimicrobial therapy is critical.⁸ However, several limiting factors exist. First, there are barriers to accessing newer β-lactams in Canada. Many are not approved by Health Canada or not marketed by their manufacturers (Table 1). Meropenem–vaborbactam and imipenem–relebactam–cilastatin are approved and marketed, and accessible through standard hospital procurement channels.⁹ Ceftazidime–avibactam and cefiderocol are not currently approved or marketed and require application to Health Canada’s SAP for access.¹⁰ For critical patient situations, SAP has a telephone line for emergency approval. If approved, medications are supplied directly by manufacturers to the requesting clinician. Because newer β-lactams may not be readily stocked by hospital pharmacies, a wait for delivery from manufacturers is often required. As these processes may take several days from initial SAP application to procurement and delivery, clinicians should work with hospital pharmacists and infectious disease specialists to develop approaches for expediting access. These include “future use” SAP applications¹⁰ and collaboration with centres that have experience in treating CPE infections and obtaining SAP approvals.

Second, challenges exist with susceptibility testing for newer β-lactams. Antibiotic susceptibility testing for most clinically significant bacteria is performed using automated platforms, with results typically available within 24 hours of organism identification. For Enterobacterales, if initial results are suggestive of carbapenem resistance, confirmatory testing and susceptibility testing for newer β-lactams should be performed. However, methodologic and logistical barriers hinder widespread adoption of this extended testing by microbiology laboratories.¹¹ Many front-line laboratories need to send clinical isolates to reference laboratories (e.g., National Microbiology Laboratory, provincial reference laboratories) for this testing, with turnaround time of at least several days. Therefore, empiric treatment of CPE infections is generally guided by the carbapenemase identified and its expected susceptibility profile to newer β-lactams (Table 1). Importantly, rapid assays for detection and differentiation of the most prevalent carbapenemases, providing results within minutes to hours, are now widely available.¹² As in our patient, who started ceftazidime–avibactam and aztreonam after rapid testing detected NDM, this can help expedite appropriate empiric antibiotic selection.

Additional strategies can optimize empiric treatment of patients with suspected CPE infections. Most hospitals screen patients for CPE colonization (by rectal swab) at admission based on risk factors, and during admission if exposure to a patient with CPE colonization occurs. Screening is performed to prevent nosocomial transmission but can inform empiric antibiotic administration if a patient with CPE colonization develops a gram-negative infection. Our patient was screened for CPE and placed in contact precautions at admission, given recent out-of-country health care exposure. However, her CPE screening swab was negative; false-negative results can occur due to sampling technique and nonrectal colonization. Furthermore, antibiotics such as aminoglycosides, tigecycline, and colistin are not guideline recommended for CPE infections and can have adverse effects with prolonged use.⁷ However, they are included in many routine antibiotic susceptibility panels and remain interim options while awaiting access to newer β-lactams. National surveillance demonstrates that susceptibility to at least 1 of these agents is generally maintained across CPE in Canada.²

Treatment durations for infections with CPE are the same as for infections with other gram-negative bacteria. The shortest effective duration is recommended; the noninferiority of shorter antibiotic courses has been well demonstrated across various infectious syndromes.¹³

This case highlights the growing threat of CPE and the challenges of treating infections with these organisms. Clinicians should be aware of CPE, given their rising incidence and limited treatment options. New antibiotics have become available, but local access and susceptibility testing are ongoing challenges that can delay their use, placing patients at risk of morbidity and mortality. Multidisciplinary collaboration is critical to improve timely initiation of appropriate therapy. We recommend that clinicians proactively collaborate with their hospital pharmacists, infectious disease specialists, and microbiology laboratory to understand logistics for antibiotic access, confirm local algorithms and anticipated turnaround times for carbapenemase detection and susceptibility testing, and select the most appropriate antibiotic regimen.

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