Abstract
Introduction: Carbapenem-resistant Enterobacteriaceae (CRE) are problematic pathogens because infections caused by these organisms are associated with significant morbidity and mortality. These organisms often harbor multiple resistance mechanisms, which makes it difficult to treat their associated infections. Treatment typically consists of intravenous antibiotics that are selected based on the specific susceptibility pattern for the pathogen. Data on the use of oral antibiotics for the treatment of infections caused by CRE are sparse. Case Presentation: In this case, a 62-year-old female presented with a chronic left leg wound infection. She previously underwent surgical debridement and skin grafting, which were unsuccessful. She was initially prescribed minocycline for the infection, but the wound got re-infected. At this time, the wound had significant surrounding erythema, drainage, and slough. A wound culture was obtained and demonstrated growth of carbapenem-resistant Enterobacter cloacae and methicillin-resistant Staphylococcus aureus. The patient was initiated on oral omadacycline, and she responded with resolution of the cellulitis and wound drainage. Conclusion: This case demonstrates that omadacycline may be beneficial as an oral medication for the treatment of complicated acute bacterial skin and skin structure infections caused by carbapenem-resistant Enterobacter cloacae.
Keywords: anti-infectives, infectious diseases, outcomes research, pharmacists, education, skin
Introduction
Carbapenem-resistant Enterobacteriaceae (CRE) present a critical problem throughout the world because infections caused by these organisms are associated with significant morbidity and mortality. 1 In the United States (US), the CRE epidemic began in 2001 with an outbreak of carbapenem-resistant Klebsiella pneumoniae, which harbored Klebsiella pneumoniae carbapenemase (KPC).1,2 Since then, KPC-producing Klebsiella pneumoniae have emerged in various communities across the country. 2 Carbapenem resistance can also occur in other species of Enterobacteriaceae, such as Enterobacter cloacae. Although the rates of carbapenem resistance in Klebsiella pneumoniae have decreased in certain areas of the country, the rates of carbapenem nonsusceptibility and resistance in species of the Enterobacter cloacae complex have increased throughout the last decade, reaching >4% nonsusceptibility and 2.5% resistance in 2014 to 2015. In addition, the proportion of isolates with intermediate susceptibility to carbapenems has been higher for species in the Enterobacter cloacae complex (46%) compared to Klebsiella pneumoniae (9%).
Infections caused by CRE are difficult to treat since the genes encoding carbapenem resistance are typically located on plasmids along with aminoglycoside and fluoroquinolone resistance determinants. 3 Due to the limited antibiotic options available, infections caused by carbapenemase-producing organisms often require treatment with intravenous antibiotics that are selected based on the specific susceptibilities. 4 Data on the use of oral antibiotics for the treatment of infections caused by CRE are sparse. In this case, oral omadacycline was used to treat carbapenem-resistant Enterobacter cloacae in a complicated acute bacterial skin and skin structure infection (ABSSSI).
Case Presentation
Written informed consent was obtained from the patient for publication of this case report and the accompanying images.
The patient was a 62-year-old Caucasian female with a past medical history of obesity, deep vein thrombosis of the left lower extremity on anticoagulation, venous insufficiency involving both lower extremities, and necrotizing fasciitis of the left lower extremity status post debridement in April 2019. After the initial debridement, her wound failed to heal appropriately. Subsequently, the patient underwent surgical debridement and skin grafting on 3 different occasions. Unfortunately, the skin grafts failed, and the wound never healed.
The patient was seen for her chronic left leg wound infection in February 2020 at the Wound Care Center. A wound culture was obtained and demonstrated growth of moderate carbapenem-resistant Enterobacter cloacae and rare methicillin-susceptible Staphylococcus aureus. She was initially prescribed minocycline 200 mg by mouth twice daily for 10 days for the infection and ondansetron as needed for nausea. She responded to minocycline with resolution of the cellulitis, but she had significant nausea despite the use of ondansetron. Once her infection improved, she was started on local wound care and compression therapy. The patient’s wound had slow improvement, and the left leg wound eventually got re-infected in May 2020. As shown in Figure 1, the wound had significant surrounding erythema, drainage, and slough on the base of the ulcer.
Figure 1.
Infected left leg wound prior to omadacycline treatment. This demonstrates surrounding erythema, drainage, and slough on the base of the ulcer.
Another wound culture was obtained and demonstrated growth of moderate carbapenem-resistant Enterobacter cloacae and methicillin-resistant Staphylococcus aureus. As shown in Figure 2, this carbapenem-resistant Enterobacter cloacae was resistant to all traditional oral antibiotic options.
Figure 2.
Left leg wound Enterobacter cloacae susceptibilities prior to omadacycline treatment. This demonstrates growth of carbapenem-resistant Enterobacter cloacae.
At that time, compression therapy was held, and she was initiated on oral omadacycline. The patient received a loading dose of 450 mg by mouth once daily on days 1 and 2. Afterward, she received a maintenance dose of 300 mg by mouth once daily from day 3 to day 10. The patient responded to omadacycline with resolution of the cellulitis and wound drainage. She then received local wound care, which involved routine debridement and compression therapy using Profore multi-layer dressings. As shown in Figure 3, the patient’s wound continued to significantly improve by July 2020.
Figure 3.
Left leg wound after omadacycline treatment. This demonstrates resolution of cellulitis and improvement in size.
Discussion
To our knowledge, this is the first case report to demonstrate successful use of oral omadacycline for the treatment of carbapenem-resistant Enterobacter cloacae in a complicated ABSSSI. Traditionally, infections caused by CRE require treatment with intravenous antibiotics. 4 Although new antibiotics, such as ceftazidime-avibactam and plazomicin, have been developed to treat carbapenemase-producing organisms, intravenous use of these medications may cause adverse reactions, administration difficulties, and increased patient cost. Treatment with oral medications is often limited by resistance genes encoded on plasmids. 3 As shown in this case, this carbapenem-resistant Enterobacter cloacae was resistant to all of the oral antibiotics that are traditionally used, so omadacycline was used for treatment.
Omadacycline received Qualified Infectious Disease Product and Fast Track designations because of the need for broad-spectrum antimicrobial medications with the ability to combat multidrug-resistant organisms. This medication received US Food and Drug Administration (FDA) approval in October 2018 for the treatment of community-acquired bacterial pneumonia (CABP) and ABSSSIs, and it is available in intravenous and oral formulations. 5 For ABSSSI and CABP, the US FDA identified the susceptibility breakpoint for Enterobacteriaceae as a minimum inhibitory concentration (MIC) of ≤4 mg/L. 6
Omadacycline is a semisynthetic aminomethylcycline derived from minocycline. 7 Its novel modification allows it to overcome traditional tetracycline-based resistance mechanisms and provides broad-spectrum coverage against aerobic and anaerobic gram positive and gram negative organisms, as well as atypical pathogens. It has also demonstrated activity against multidrug-resistant organisms, such as CRE.
The approval of omadacycline for ABSSSI was based on a phase III non-inferiority trial, which compared it to linezolid. 8 Patients in this study were initiated on the intravenous formulation and allowed to transition to the oral formulation after 3 days. Although this study showed non-inferiority to linezolid for ABSSSIs, only 15.4% of patients had a polymicrobial mixed gram positive and gram negative infection. In addition, patients with an infection caused solely by gram negative pathogens were excluded because linezolid was used as the comparator.
A surveillance study assessed the activity of omadacycline among clinical isolates from the US and Europe from 2016 to 2018. 9 Omadacycline was tested against 49,000 bacterial isolates from 73 different medical centers. In this study, carbapenem-resistant Escherichia coli had an MIC50 and MIC90 of 1 and 2 mg/L, respectively. However, carbapenem-resistant Klebsiella pneumoniae had an MIC50 of 4 mg/L and an MIC90 of 8 mg/L. For species in the Enterobacter cloacae complex, omadacycline had an MIC50 and MIC90 of 2 and 4 mg/L, respectively. Against ceftazidime-non-susceptible Enterobacter cloacae complex isolates, omadacycline was less active with an MIC50 of 2 mg/L and an MIC90 of 8 mg/L. None of the Enterobacter cloacae complex isolates were specifically classified as carbapenem-resistant in this study.
Despite the lack of data available regarding the use of omadacycline for carbapenem-resistant Enterobacter cloacae infections, this patient was treated with oral omadacycline based on the data available in Enterobacter cloacae and carbapenem-resistant Escherichia coli infections. Repeat wound cultures were not obtained as documentation of bacterial clearance because chronic wounds caused by venous insufficiency can remain colonized with bacteria. However, this patient clinically responded to oral omadacycline with resolution of the cellulitis and wound drainage. Therefore, this case highlights the successful use of oral omadacycline for the treatment of a complicated ABSSSI caused by carbapenem-resistant Enterobacter cloacae.
Conclusion
Omadacycline may be beneficial as an oral medication for the treatment of complicated ABSSSIs caused by carbapenem-resistant Enterobacter cloacae. Additional data are needed to investigate and confirm our findings.
Footnotes
Authors’ Note: The data represented in this manuscript were presented as a poster at the virtual ASHP Midyear Clinical Meeting 2021 on December 8, 2021.
Data Availability: The data used to support the findings of this study are available from the corresponding author upon request.
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Rajinder P.S. Bajwa has served on an advisory board for Paratek Pharmaceuticals, which is the company that developed omadacycline. All of the other authors declare that there are no additional conflicts of interest.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval: This work was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans, and the case was cleared through the D’Youville College Institutional Review Board.
ORCID iDs: Dylan C. VanDuyn 
https://orcid.org/0000-0002-8860-417X
Mario V. Beccari
https://orcid.org/0000-0003-4416-8035
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