Why are we afraid of Acinetobacter baumannii?

Multidrug-resistant (MDR) Acinetobacter baumannii, defined as resistance to three or more different antibiotic classes, is rapidly becoming a focus of attention of the medical and scientific communities [1]. The Infectious Diseases Society of America (IDSA) identified A. baumannii among the top seven pathogens threatening our healthcare-delivery system and as a prime example of unmet medical need [2]. The clinical impact and molecular basis of the ‘MDR phenotype’ have also made A. baumannii a study of ‘bug and drug’ interactions at every level, as summarized elegantly herein by Gootz et al.[3]. We hope to address the following questions in this editorial: why are we so afraid of MDR A. baumannii and is A. baumannii becoming a very ‘successful pathogen’?

MDR A. baumannii & the limits of antibiotic therapy

The particular challenge with A. baumannii is the integration, expression and regulation of many different genetic determinants that result in a MDR phenotype. For instance, the presence of OXA- and metallo-β-lactamases in the context of constitutively expressed, broad spectrum, Acinetobacter-derived cephalosporinases insures resistance to all β-lactams, including carbapenems. A critical role is played by insertion sequences (e.g., ISAba1), which act as strong promoters of β-lactamase production and contribute signi-ficantly to other resistant pheno-types. Adding to this is resistance to quinolones, mediated by single point mutations in the quinolone resistance-determining regions of gyrA and parC, and upregulation of efflux pumps, as shown in Tables 1 and 2 in the paper by Gootz et al. Thus, intrinsic and acquired mechanisms of resistance to antibiotics abound [3]. Of greatest concern is the report of resistance to colistin, our ‘last resort’ antibiotic [4].

The degree of complexity of the ‘resistosome’ [5] in A. baumannii is evident in the early analysis of the genome of a MDR A. baumannii strain, AYE, performed by Fournier et al.[6]. An 86-kb resistance island harboring 45 different resistance genes was identified. Given this tremendous capacity for acquiring antibiotic resistance determinants, clinicians may be left with few, if any, effective therapeutic options. It is also unclear whether the results of carefully performed in vitro studies of susceptibility to certain classes, or combinations of antibiotics, always translate into effective therapeutic choices [4]. This causes worry that there is a great deal of genetic adaptability in A. baumannii.

Physicians often dismiss A. baumannii. as an ‘opportunistic’ pathogen. The implication of this epithet is that A. baumannii. is not highly virulent and that its ability to cause disease is determined by underlying ‘deficiencies’ in the patients it colonizes and infects. Epidemiologically, it is clear from retrospective studies that there are groups at a higher risk of infection and colonization with A. baumannii. (i.e., those who are critically ill in intensive-care units, subjected to invasive treatment and support modalities, and exposed to broad-spectrum antibiotics). These populations are growing fast and probably represent the cohort most dependent on effective antimicrobial therapies. Less clear is what makes these patients more vulnerable to A. baumannii. and the additional impact that MDR A. baumannii. has on their already fragile state. Clinically, fulminant pneumonia, disseminated intravascular coagulation and a severe sepsis syndrome may occur with A. baumannii infection. By contrast, there are patients who suffer bacteremia without any clinical signs or symptoms of sepsis.

Regrettably, our understanding of the host response to A. baumannii is rudimentary. There is incipient information from animal and in vitro studies that begin to delineate the interactions between the host and A.baumannii. Lipopolysaccharide from A. baumannii elicits a strong response of the Toll-like receptor (TLR)4 signaling system, while the acute inflammatory response and neutrophil dysfunction impair the host response to respiratory infection with this organism [7–10]. The integration of these and other immune mechanisms in vivo remains to be defined. Characterizing these responses in the elderly, and in chronically and critically ill patients, may reveal whether there are immune and genetic factors underlying susceptibility to infection or col-onization with A. baumannii.

Recent attention is also focusing on bacterial characteristics, beyond the MDR phenotype, which may determine the course of infection and colonization of A. baumannii[11]. For instance, acyl-homoserine lactone-signaling molecules, involved in a key mechanism that permits coordinated cell–cell interaction (‘quorum sensing’) and, thus, regulate biofilm formation, are present in A. baumannii and have recently been characterized in detail [12]. Experimental models of A. baumannii biofilm formation allow a glimpse of the molecular and genetic mechanisms involved, and the capacity of clinical isolates of MDR A. baumannii to form biofilm has been confirmed [13,14]. A recent report analyzed the formation of biofilms among 92 clinical isolates of A. baumannii from Spain. The isolates that readily formed biofilms were associated with catheter-related infections, whereas non-biofilm-forming isolates were associated with respiratory infection or colonization [15]. It is hoped that comparative genomics will also permit the systematic analysis of the genetic determinants of biofilm formation, among other mechanisms of virulence in A. baumannii[11,16].

Why such a ‘successful pathogen’?

In the final analysis, what really makes MDR A. baumannii so remarkable is its frequent and increasing occurrence as a nosocomial pathogen on a global scale [17]. Often reported as the cause of outbreaks, A. baumannii readily colonizes healthcare environments, leading to high rates of endemicity. One of the most poignant examples is the widespread occurrence of MDR A. baumannii among personnel returning from military operations in Iraq and Afghanistan [18]. An analysis summarizing A. baumannii outbreaks and the various strategies applied to limit their spread suggests that control is most successful when a common environmental source is identified [19]. Unfortunately, these types of events represent a small fraction of contemporary instances of A. baumannii infection and colonization. Outbreaks without a common source and endemic infection and colonization often necessitate ‘bundle’ approaches, including strict isolation, hand washing and environmental decontamination. These measures are expensive, logistically demanding and need validation in prospective trials. Alarmingly, a recent study showed a reduction in the bactericidal effects of nosocomial disinfectants against A. baumannii in the presence of organic material (3% bovine serum albumin) and decreased susceptibility to chlorhexidine after repetitive passages with this agent [20]. Just as it challenges our existing modalities of antimicrobial therapy, MDR A. baumannii seems poised to defy our conventional approaches to infection and environmental control. In our opinion, this is a clear demonstration that A. baumannii has coevolved with our current healthcare delivery system to achieve the status of a ‘highly successful human pathogen’. It is perfectly adapted to resist our antibiotics and disinfectants, take advantage of our life-supporting invasive devices to cause disease in those who are less able to withstand it, and exploit our every contact with patients as an opportunity for transmission. Unless we can find a way to undermine the success of this pathogen, it is safe to conclude that A. baumannii will be with us for the long haul.

Financial & competing interests disclosure

The Veterans Affairs Merit Review Program and the NIH (RO1 AI072219) support the work of RA Bonomo. The authors have 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.

No writing assistance was utilized in the production of this manuscript.