A formidable foe: carbapenem-resistant Acinetobacter baumannii and emerging nonantibiotic therapies

KEYWORDS:

• Carbapenem-resistant Acinetobacter baumannii
• therapies
• hospital-acquired infections
• vaccination
• decolonization

The emergence of carbapenem-resistant Acinetobacter baumannii (CRAB) has become a serious global health concern. In the United States, nearly half of A. baumannii strains isolated from patients with healthcare-associated infections are resistant to carbapenems [1]. Mortality in patients with CRAB infections is high (approximately 33%) and treatment options are limited [2]. The cost of treating CRAB is considerable and makes up part of the estimated $2.2 billion spent in the United States annually on antibiotic-resistant infections [3]. Despite a growing body of research including the use of synergistic combinations from two or three different classes of antibiotics, the optimal treatment of CRAB remains uncertain. Indeed, a recent study that included over 300 cases of CRAB found combination therapy was not superior to monotherapy [4]. The topic of antibiotic therapy for CRAB has been comprehensively reviewed [5]. Shin and Park also recently described the complex mechanisms of antimicrobial resistance in A. baumannii [6].Therefore, this article describes some emerging nonpharmacologic approaches for CRAB including fecal microbiota transplantation (FMT), vaccines, bacteriophage, and monoclonal antibodies (MAbs) as well as recommends areas where further research is needed to tackle this ‘formidable foe.’

Many patients admitted to intensive care units (ICUs) harbor CRAB in their intestinal flora, especially those with prior exposure to carbapenems [7]. Thus, there is growing interest in using FMT as a method of decolonization. FMT involves the administration of screened, healthy donor stool into a patient’s gastrointestinal tract, either into the colon by enema or colonoscopy, or into the upper small intestine by nasojejunal tube or swallowed capsules. FMT has proven to be very effective for treating recalcitrant Clostridium difficile infections (CDIs). In one such case, a patient who was chronically colonized with several multidrug resistant (MDR) organisms including CRAB and suffered recurrent infections from them developed CDI. The patient underwent FMT, which successfully resolved the CDI and resulted in a reduction in post-FMT MDR infections [8]. This case and others provides a proof-of-concept for using FMT to eradicate CRAB colonization of the lower gastrointestinal tract. Recently, Leung and colleagues used whole metagenome sequencing data from 8 FMT donor–recipient pairs to identify 37 and 95 AMR genes acquired by or removed from FMT recipients, respectively [9]. Specifically, they observed the loss of genes belonging to the extended-spectrum β-lactamase (ESBL), glycopeptide, and quinolone antimicrobial classes along with the polymyxin resistance gene PmrC-F. Although no large, randomized controlled trials have been conducted, preliminary data for using FMT as a decolonization strategy for patients harboring CRAB in the gastrointestinal tract appear promising. However, the cost of FMT may be a limitation, especially if payers refuse to cover the procedure.

Vaccination against MDR pathogens like CRAB is an attractive concept because of the potential for less antibiotic exposure and the generation of herd immunity in patients most susceptible to CRAB infections, such as the immunocompromised or those in ICUs. Several potential A. baumannii antigens have been identified including outer membrane vesicles (OMVs), outer membrane protein A (OmpA), auto-transporter (Ata), biofilm-associated protein (Bap), K1 capsular polysaccharide, and Poly-N-acetyl-β-(1–6)-glucosamine (PNAG) [10]. Currently no vaccines for CRAB have progressed beyond phase I clinical development. One candidate vaccine that uses Gram negative bacteria-derived OMVs, which are highly immunogenic and induce a robust response against bacterial infection, was found to protect mice from a lethal challenge with a clinically isolated A. baumannii strain [11]. One obstacle for vaccines against CRAB is the sequence variability of the antigens and their absence in circulating CRAB strains may result in poor cross-protective efficacy against strains that cause hospital-acquired infections (HAIs). This is due to mutations that can occur because of selective immunological pressure, leading to down-regulation of the target antigens [10]. Thus, identifying highly conserved antigens from CRAB strains that cause HAIs needs to be a research priority. Another challenge is identifying a patient population to include in a clinical trial of vaccine efficacy that has a high short-term risk for developing a CRAB infection.

Bacteriophages (aka phages) are viruses that invade and kill bacteria by lysis but do not harm human cells. First discovered in the early twentieth century, phages were studied and used primarily in Eastern Europe and the Soviet Union due to the scarcity of antibiotics. Phages are specific for different bacteria, binding to receptors on bacterial cell walls. This is in contrast to antibiotics, which indiscriminately kill normal bacterial flora and disrupt the human microbiome. Recent case reports have led to renewed interest in the potential of phage therapy for CRAB infections. In one report, two 4-phage cocktails were administered intravenously and into 3 intra-abdominal drains for a patient with necrotizing pancreatitis and a CRAB pancreatic pseudocyst infection [12]. The result was a cure of the infection and a complete clinical recovery. In another case, phage therapy was used to treat a craniotomy site infection due to a MDR A. baumannii [13]. Based on antimicrobial susceptibility testing, the patient was treated with colistin, azithromycin and rifampin but no clinical improvement occurred. The researchers then administered phage therapy intravenously for 8 days. Although fever and leukocytosis persisted, there were no further signs of infection at the craniotomy site after debridement, and the skin flap healed well. Unfortunately, the patient’s family decided to withdraw care before the second phage cocktail could be administered and the patient died on hospital day 20. These case reports raise hopes for the potential of treating CRAB infections with phages. However, there are several limitations that must be overcome before phage therapy can be widely implemented. Unlike antibiotics, phages evolve over time as their genetic material mutates. This makes approval by governmental regulatory agencies problematic as they generally do not allow treatments that change while inside the human body. Other concerns include the potential for host inflammatory responses and a negative impact on the gut microbiome. Further investigation of phage therapy for treating CRAB infections, including randomized clinical trials, is needed along with ways to optimize their production on a larger scale.

Despite the successful development and use of MAbs for a variety of medical conditions including cancer and autoimmune diseases, only a few antibody therapies have been licensed for infectious diseases (e.g. bezlotoxumab for prevention of recurrent CDI). Nevertheless, it is important to note that the human immune system primarily developed as a mechanism to fight infections, not cancer or rheumatoid arthritis. In contrast to antibiotics, antibacterial antibodies do not impact the human microbiome, have less likelihood to promote resistance, and can potentially be given as a single injection. MAbs might also be given concurrently with antibiotics, which could reduce the total duration of antibiotics and the risks associated with antibiotic therapy. In 2001, Goel and Kapil reported that MAbs against iron outer membrane proteins of A. baumannii were bactericidal by blocking siderophore-mediated iron uptake [14]. More recently, Nielson et al. developed a MAb called C8 that targets a capsular carbohydrate of A. baumannii [15]. Using a mouse model, the researchers found that a single dose of C8 improved survival in lethal bacteremic sepsis and aspiration pneumonia caused by a clinical strain of CRAB. Moreover, C8 was synergistic with colistin and survival was significantly improved compared to monotherapy. When A. baumannii was serially passed in vitro in the presence of C8, no loss of MAb binding to the bacteria was observed, but less virulent mutants did evolve that were more susceptible to macrophage uptake. While significant obstacles remain in identifying appropriate targets and improving their effectiveness, developing MAbs to treat CRAB infections appears to be a realistic goal based on our current understanding of their safety and pharmacological properties.

In conclusion, CRAB infections are a major challenge for physicians to treat and frequently lead to poor outcomes. While new antibiotics are desperately needed, the alternative nonantibiotic therapies described in this article would greatly strengthen our armamentarium in the arms race against CRAB. Despite their potential, these agents are still a long way off from widespread use in the clinic and for replacing antibiotics as the mainstay for treating CRAB infections. Therefore, innovative research on both traditional (i.e. antibiotics) and nontraditional therapies for CRAB must continue and be a high priority that is recognized by all relevant stakeholders. To quote the Nobel laureate Dr. Joshua Lederberg, it remains a battle of ‘our wits versus their genes.’

Declaration of interest

R Watkins has received a grant and serves on an advisory board for Allergan. The authors has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

The manuscript was not funded.