Though not discussed heavily in major media outlets outside of medical journals, the nosocomial (hospital-acquired) bacteria Acinetobacter baumannii (AB) has been gaining resistance to commonly prescribed antimicrobials. Also known as multidrug resistant (MDR) bacteria, these pathogens sources a multitude of infections in already-ill hospital patients as antibiotics are used to no avail. Such resistance can be briefly explained by the use of several transmembrane proteins of the bacteria to expel antibiotic threats while simultaneously allowing for rapid genetic mutations. While not an immediate threat to the global health community, Acinetobacter baumannii and additional MDR pathogens necessitate new and effective solutions that are able to overcome future multidrug resistance. As of yet, upcoming antibiotic therapies are still being extensively researched, but they are reaching several degrees of successful treatment, as well as new techniques, including monotherapies and synergistic drug use. It is imperative that further research into effective, and most importantly, long-term treatments to MDR pathogens be conducted in the near future to avoid a global health crisis that may have everlasting consequences on the healthcare industry and human health.
Acinetobacter baumannii is an aquatic, aerobic, pleomorphic, gram-negative, bacillus that prefers to colonize aquatic environments; it can often be found inside intravenous or irrigating liquids and embed infections in the sputum, respiratory, urinary tracts or in wounds.1 Surprisingly, they are most common in intensive care units as opposed to medical or surgical wards.2 The history of the aforementioned strain of bacteria stems from the discovery of the genus Acinetobacter in 1911, when Dutch microbiologist Beijerinck isolated an organism called Micrococcus calcoaceticus from a calcium-acetate-containing sample of soil; scientists Brisou and Prévot later separated the non-motile microorganisms from the motile ones to establish the genus Acinetobacter.3 Later on, the species A. baumannii was established in 1986 as it was the most common strain in clinical samples.2 In April 2013 in the outreaches of western China, 36 workers were infected with ammonia poisoning during an ammonia leak incident, with five of them containing pulmonary infection and chemical pneumonitis; these five were then isolated, where 2 of the 5 patients died later on.4 Furthermore, the research article written by Junyan Qu and his cohort explicated on how the samples of these five patients revealed an outbreak of AB due to possible trauma, hyperimmunity, or the coinfection of other bacteria; this outbreak was the first of this specific species of the genus Acinetobacter but it was fortunately contained by the hospital staff.4 Another alarming concern arose after the Institute for Hygiene and Infectious Diseases of Animals in Giessen, Germany, receive 137 veterinary samples from universities pertaining to the related 137 hospitalized animals; the discovery of AB in these samples revealed that the aforementioned strain of bacteria can also be a nosocomial pathogen in not only humans but also animals, raising concerns for cross infections between animals and humans.5 These recent incidents, in addition to many more unmentioned ones, has raised concerns about Acinetobacter baumannii and the presence this species of bacteria has to affect patients in medical setting. In addition to their threat in hospitals and ICU’s, AB is an invasive and rapidly adapting pathogen that can easily evade many antibiotics, utilizing mechanisms, several of which will be discussed later on in this article, to grow and spread.
Classification and Background
Acinetobacter baumannii is an aerobic, non-fermenting, gram-negative Coccobacillus, emerging as a prominent nosocomial pathogen with an inherent resilience to commonly prescribed antimicrobials, often acting as an opportunistic pathogen.6 In simpler terms, AB causes hospital-acquired infections by thriving in weakened immune systems, which are readily available in common surgical rooms and ICUs in the form of secretions, surgical incisions, or wounds. Acinetobacter can inhabit part of the bacterial growth of the skin, particularly in moist regions such as the axillae, groin, and toe webs, and up to 43% of healthy adults can have colonization of skin and mucous membranes.7 In fact, colonization is higher among hospital personnel and patients due to skin ruptures and wounds, as it is part of the nature of healthcare. Moreover, AB typically colonizes aquatic environments, leading it to deal serious damage to high-fluid organs that lie in the respiratory tract and the urinary tract, and is often isolated from respiratory support equipment.8 In regards to these characteristics of A. baumannii, a gram-negative Coccobacillus refers to the cellular composition of the bacterium; specifically, this bacterium contains a thin peptidoglycan cellular wall sandwiched between two bacterial membranes. A Coccobacillus bacterium is the combination between a cocci (spherical-shaped) and bacilli (rod shaped). A. baumannii distinguishes itself as aerobic and non-fermenting, meaning that it survives by utilizing oxygen as the main source to produce energy (in the form of ATP) in its mitochondria; however, it is not able to survive in an anaerobic environment via fermentation. This species falls under the class of Gammaproteobacteria, and is prevalent in soil and water as a mineralizer (which explains its preference for high-fluid organs). In addition, the genus currently comprises of 34 species of which A. baumannii holds the greatest significance in the clinical aspect.9 Infections caused by AB include blood-stream infections, urinary tract infections, meningitis, ventilator-associated pneumonias, and wound infections; many of which can be indirectly and directly linked to the colonization of AB in intravenous solutions, ventricular drainage tubes, use of a central venous catheter, and several other factors that work in tandem with the bacterium’s aquatic preferences.6,8 In addition, the nature of Acinetobacter baumannii makes it one of the six most important multidrug-resistant microorganisms in hospitals worldwide, as the majority of its infections are caused by two main population clones with worldwide distribution.10 These characteristics demonstrate how prevalent MDR bacteria can be and how paramount discovering an effective and unique solution should be.
For several decades, antimicrobials have been used to treat a wide variety of bacterial infections. However, such drugs have been overused, causing a rise in the phenomenon known as multidrug resistance. Acinetobacter baumannii is famously known as one of the leading nosocomial pathogens that exhibit such resistance to antimicrobials. On a general scale, several studies have demonstrated that the crude mortality rates in patients with AB varied between 30 and 76%, and the factors that contributed to an undesirable prognosis include immunosuppression, severity of underlying illness, inappropriate antimicrobial therapy, septicemia, prior antibiotic exposure, and most notably of all, drug resistance.6 Efforts to relieve these mortality rates have led to intense research done on the nosocomial epidemiology of A. baumannii. In a 1998 study, conducted by Dr. Daniel Villers, designed to assess the epidemiological risk AB, the researchers concluded that such nosocomial infection was a complex coexistence of endemic and epidemic infection, where the endemic infections were favored by the selection pressure of intravenous fluoroquinolones (or any antimicrobial drug for that matter) and the epidemic was primarily caused by the constant use of a single operating room in the tested hospital.11 Inspecting this issue through a global lens, Italy is one of the European countries with increasing spread of antimicrobial-resistant microorganisms, often resistant to multiple drugs and with high antibiotic consumption in a hospital setting. Several factors, such as antimicrobial consumption, colonization of resistant bacteria, resistance mechanisms that vary by species, and infection control strategies, including screening policies, may play a role in the prevalence of antimicrobial-resistant pathogens in the hospital setting.12 In addition to Southern Italy, a study conducted in North China, over a 65-month period, measured the molecular epidemiology of a specific gene in A. baumannii, and concluded that, because of its multidrug resistance, the specific gene transformed the bacteria into highly infectious in the hospital setting.13
Furthermore, one feature of AB is its ability to cause outbreaks, as seen in several cases. One such case occurred in France from July 2003 to May 2004, in which 290 cases of infections and/or colonizations occurred in 55 health care facilities located in 55 different departments.14 From a group of 217 patients for whom clinical data were available, 73 (33%) suffered from infection and 144 (67 %) were colonized. Among the infected patients, there were 19 (26 %) deaths that were directly attributed to AB infection.14 Similarly, in a study conducted from April to November of 2014, a certain burns unit saw 77 patients acquiring MDR-AB at a rate of 30% after 28 days, and the median hospital stay was increased due to said infection by 12 days.15 In all of the MDR-AB isolates from the patients, a specific gene (blaOXA-23) was recognized as contributing to the bacteria’s environmental resistance. Moreover, in a 1999 study done on a group of 192 healthy hospital volunteers, 40% of the volunteers contained a strain of Acinetobacter on at least one body site.16 In the majority of these studies, antibiotic consumption as prescribed by physicians, while in good faith and intention, was in excess enough to encourage rapid colonization of multi-drug resistant Acinetobacter baumannii.
In addition, the infectious nature of AB has been noted partially because of its habitat in soil and water, which in turn introduces the bacteria to a local food supply, as food is known to be a source for gram-negative rods, such as Escherichia coli. According to a study conducted by John Berlau and colleagues on the frequency and distribution of the Acinetobacter genospecies, 17% of vegetables sustained Acinetobacter in small numbers, and A. baumannii was one of the species more frequently found.14 The A. baumannii—A. calcoaceticus (another opportunistic nosocomial pathogen of the genospecies Acinetobacter) complex accounted for 56% of all strains isolated from fruits and vegetables and were found in apple, melon, beans, cabbage, cauliflower, and several other commonly consumed produce.14 According to Berlau et al., hospital food could be a potential incubator for A. baumannii. The more alarming issue with this result stems from research done on digestive-tract colonization in patients in a hospital setting, with colonization rates reaching as high as 41% in ICUs.14 In order to relieve the patient of any further debilitating infection, commonly-prescribed antibiotics, such as carbapenems, are utilized to no effect. The resistance rates of AB to last-resort antimicrobials as carbapenems and colistin are on the rise, and healthcare facilities act as a reservoir for resistant AB.9 These trends should not only inform current treatment options of serious infections, but also approaches to infection control.
The antimicrobial resistance of A. baumannii has been well researched and documented, leaving hospital physicians and healthcare facilities to implement desperate attempts at infection control. The methods include prescribing ineffective antimicrobial drugs, such as fluoroquinolones and carbapenems. To combat the spread of multi-drug resistant pathogens, the World Health Organization (WHO) implemented the multimodal hand hygiene improvement strategy in 2010. This included a set of management goals (a healthcare facility policy review, a dedicated budget for hand-hygiene agents, and a survey of the staff’s tolerability of alcohol-based handrub), training and education (regular training for all workers, research and collaboration, antibiotic stewardship, and e-learning), evaluation and feedback, and several systemic changes to encourage and/or enforce proper hand hygiene procedures.17 Studies have concluded that this strategy can be effective in reducing general nosocomial infections if taken upon all staff members. The importance of infection control is demonstrated by the severity of A. baumannii in critically ill patients, in which patients infected with MDR strains of any organism suffer organ dysfunction and longer ICU stays less frequently, as well as facing decreased mortality rates as compared to patients infected with a strain of Acinetobacter (when severity of the illness is controlled).18 Another method of infection control includes constant surveillance, as seen by a 2013 study conducted at a Seoul national university hospital, where Carbapenem resistant Acinetobacter baumannii (CRAB) was subject to active surveillance culture at an ICU. When active surveillance culture of CRAB and contact precaution for the patients of positive results were applied in a medical ICU, the rate of new CRAB bacteremia was lowered and the time between new CRAB bacteremia and ICU admission was lengthened.10 This study also utilized effective infection control policies and practices.
Another form of infection control can be observed through the local food supply. Widely distributed in soil and water, A. baumannii grows at various temperatures and pH environments and uses a vast variety of substrates for its growth. In nature, Acinetobacter is most commonly found in soil and water, but has also been isolated from animals and humans. Methods to control the use of such infection, such as sterilizing or intensively cleaning produce (for hospital food), or an acute awareness of the environment of AB can greatly reduce the number of cases of infection. However, as this is famously an issue in hospitals, the best form of prevention has to be burdened on the healthcare facility itself.
The rapid development of multidrug resistance amongst strains of Acinetobacter baumannii can be accredited to the inherent physiological mechanisms present in this species of the Acinetobacter family. Asides from mutations and intrinsic genetic inheritance to a variety of antibiotics, AB possesses multiple efflux systems that are characteristic of many rapidly developing gram negative bacteria. In an article written by Bruno Périchon, a researcher from the Pasteur Institute, and his peers, it’s thoroughly explained how efflux pump systems possess multiple transmembrane proteins that can not only expel imminent threats to the strain of bacteria but can also facilitate genetic mutations or new mechanisms to combat antibacterial invaders.19 So far, their research has uncovered three out of the five bacterial efflux pump families: RND, MFS, and MATE. They cited how each family is organized based on different components, such as the periplasmic adaptor protein, and the different drug resistances that it can develop .
Aixin Yan and his fellow researchers at the University of Hong Kong illustrate the physiology and function of the the RND pumps: the pumps generally possess three protomers, or proteins that initiate chemical processes that convert monomers into complex macro molecules through polymerization.20 The first protomer displays a crystal structure and is widely known to exist in tight conformation (T), as opposed to the second protomer, which exists an open conformation (O) and functions to expel substrates from the bacteria. Yan then delves into the mechanisms that allow RND pump to excrete imminent threat to the Acinetobacter baumannii isolate: the first protomer helix, which is attached to its structure, inclines into the second protomer and blocks the exit of substrates from the substrate pocket, Yan also introduces a third protomer, which exists in loose conformation (L) and possesses a second binding site that is designated for any additional substrates entering the RND pump. Yan’s entry then concludes by expounding on how the three protomers function in a rotational formation: the substrates enters through the top funnel to reach the empty pocket and the efflux pump is coupled with proton transport across the cell membrane to activate the process.
Amongst the RND pumps, the first and most prominent one researched by Périchon and his team was the AdeABC system, which consists of the adeABC operon, which encodes the AdeA MFP, the multidrug transporter AdeB, and the AdeC outer membrane factor.1 The cohort compared natural isolates of AB to the mutated ones in the experiment and realized that the operon is not present in natural strains of AB and therefore are thought to be derived from the overexpression of this pump. The operon expression revealed to be regulated by the AdeR-AdeS protein system whose purpose is to extrude aminoglycosides, β-lactams, fluoroquinolones, tetracyclines, tigecycline, macrolides, chloramphenicol, and trimethoprim. In the team’s experiment, the signal for the transcription of the operon was received by the AdeS protein; however, the role of AdeR and the binding site of AdeS have not been discovered thus far. The protein system’s relation to the adeABC operon was deduced by the researchers to be mutations in the protein system resulting in the expression of the AdeABC system . However, Périchon’s team postulated that a mutation in AdeS induces an inconsistency in the dephosphorylation of AdeR, resulting in an active system.
The two other less known RND pumps still play an important role in equipping isolates of A. baumannii with multidrug resistance. Yan’s experimentation shows that the AdeIJK system is correlated exhibiting resistance to β-lactams, such as ticarcillin, cephalosporins, and aztreonam. Another RND efflux pump system, AdeFGH, is encoded by the operon adeFGH and shows multidrug resistance when overexpressed; it incorporates resistances to fluoroquinolones, chloramphenicol, trimethoprim, and clindamycin and decreased susceptibility to tetracyclines, tigecycline, and sulfamethoxazole without affecting β-lactams and aminoglycosides.20
Non -RND pumps, like the MFS and SMR efflux pumps, have their structures generalized by research completed by Périchon and his team that covered the EmrD transport protein of E. coli. The crystal structures were shown to be composed of twelve protein helices with four helices facing the exterior of the cell membrane and the remaining helices composing the interior cavity of the transport protein. The internal cavity held hydrophobic residues to allow hydrophobic molecules to pass through the cell membrane. The system followed an alternating access model where antibacterial invaders can enter through either the periplasm or the cytoplasm .
The Acinetobacter baumannii holds three main non-RND pumps. CraA (for chloramphenicol resistance Acinetobacter) was found by Yan and his peers to be homologous to the MdfA efflux pump of Escherichia coli, which only transports and confers resistance to the antibiotic chloramphenicol. Yan’s team also uncovered AmvA, an MFS transport system, that possesses a 14 protein transmembrane system to expels dyes, disinfectants, and detergents; the only antibiotic found to be affected was Erythromycin. The third main non-RND pump discovered by the University of Hong Kong’s research team was AbeM, a MATE efflux pump that ejects aminoglycosides, fluoroquinolones, chloramphenicol, trimethoprim, ethidium bromide, and dyes.
Other proteins distinct to gram-negative species of bacteria or A. baumanii itself also confer multidrug resistance. In a comprehensive study conducted by Ian T. Paulsen, a student researcher at the University of Leeds in the School of Biomedical Sciences, and his fellow colleagues, Acel proteins were shown to directly interact with chlorhexidine and regulate its expulsion through energy dependent mechanisms relying on either efflux pumps.21 The study also exhibited how BTP domain proteins assisted in developing resistance to biocides and fluorescent dyes. Anna Sara Levin and her fellow researchers at the Department of Infectious Diseases in the University of São Paulo conducted experimentation to prove that in conjunction with these proteins, A. baumannii strains that carried the blaOXA-51-like, blaOXA-23-like gene, the blaOXA-143-like, or the blaIMP gene display resistance to the antibiotics meropenem, rifampicin, and fosfomycin.22 Additionally, experimentation monitored by Andrew Carter and his fellow scientists at the MRC Laboratory of Molecular Biology in Cambridge, UK, discovered that genes for aminoglycoside-modifying enzymes in class 1 integrons(gene cassettes that although immobile by themselves, they can be mobilized to other integrons) are rife in multidrug-resistant AB strains.23 As for antibacterial aminoglycosides, Carter’s experimentation found that rRNA methylation will prevent aminoglycosides from successfully binding to their targets. Another common gene the scientist found is the tet(A) to tet(E) determinants, which can encode multidrug efflux pumps or code for ribosomal protection alongside tet(K), tet(O), and tet(M) When the cohort mutated the genes gyrA and parC genes, results showed that quinolones were prevented from binding to their targets.
Despite the various general mechanisms already present amongst A. baumannii strains, there are still many antibacterial agents that can prove effective. However, many isolates of AB manage to undergo posttranslational modification by their enzymes in order to counteract antibacterial invaders.
MRC Laboratory described polymyxins as positively charged antimicrobial peptides that target the anionic lipopolysaccharide molecules in the outer cell membranes of gram-negative bacteria, leading to disassociation between the outer cell membrane and inner cell membrane as they begin to directly interact, eventually leading to cell death.23 The Department of Microbiology at Monash University entailed how resistance to polymyxins is developed in strains of A. baumannii through modifications to the lipid A, which will diminish the charge based interaction between polymyxins and lipopolysaccharide molecules.23 Carter and his team noted that even though some strains can deploy resistance mechanisms to nullify this type of interaction in lipid A, which is an endotoxic component of the outer lipid membrane that combats antibacterial agents in many gram negative bacteria, resistance to these types of antimicrobial peptides are extremely rare.
Monash’s microbiology department also detailed the interaction between A. Baumannii isolates and colistin, which differs from polymyxin B by a mere amino acid. This type of peptide exhibited a similar mechanism to polymyxins by which it binds and then permeabilizes the outer membrane, disassociating the outer cell membrane and leading the inhibition of the cell membrane function. This peptide makes this gram negative strain of bacteria vulnerable as an essential part to the survival of many gram negative bacteria is to form a highly selective barrier to potential antibiotics. In response to colistin, AB isolates have developed various responses to evade the effects of this peptide. Experimentation by Crystal L. Jones and her colleagues at the Walter Reed Army Institute of Research produced results that proved that an addition of phosphoethanolamine and galactosamine through posttranslational modification done by the bacteria’s enzymes instills a mechanism that helps this portion of the cell membrane combat colistin and other drugs.24 Jones’s team certified that the mechanism for the insertion of phosphoethanolamine and galactosamine was indeed posttranslational modification and not a genetic mutation as there was no evidence of a nucleotide polymorphisms (a kind of genetic sequence variation). Another modification was connected to the synthesis of lipid A. The gene lpxA is hypothesized by Carter and his research team to code for the acetylglucosamine acyltransferase which initiates the first step in the synthesis of lipid A; mutations in this gene can prevent the synthesis of lipid A, thus producing colistin resistance as no charged based interactions can occur with the positively charged peptide. However, as discussed earlier, the lack of lipid A will reduce the fitness of colistin resistant strains.
Birgit Schellhorn and fellow student scientists at the University of Basel found Acinetobacter baumannii to be sensitive to sodium tellurite, although the expression of the gene Tpm in many bacteria as a response to sodium tellurite detoxified the chemical through methylation, thus producing the unsustainable dimethyl telluride.25 On the other hand, the antibiotic tigecycline, although old and considered to be somewhat outdated, was found by the team to easily evade a bacteria’s defenses by inhibiting the 30S ribosomal subunit. This subunit is responsible for proofreading aminoacyl transfer RNAs and disposing those that don’t match the codon of mRNA and it translocates the tRNA with the associated mRNA by a codon, ensuring accuracy in the genetic code.26 Therefore, the lack of a functional 30S subunit can lead to errors in the genetic message of AB strains, which may possibly result in dysfunctional structures, thus leaving the isolates to be more susceptible to antimicrobial agents. Despite the evasiveness of tigecycline, strains of AB found ways to dispose of this antibacterial agent in the Schellhorn’s team’s experiment, such as the AdeABC mentioned previously. After thorough experimentation, Schellhorn and her cohort concluded that there is another alternative tigecycline resistance mechanism as 60% of isolates that still had the gene adeR deleted still successfully combated the antibiotic. They also assumed that the deletion of nucleotide 311, which leads to a premature stop codon, making this protein variant of Trm ineffective, yet leading to overwhelming tigecycline resistance as the functional Trm strains showed susceptibility to tigecycline, as opposed to the mutant variants, which showed no susceptibility.
Novel Antibiotic Therapies
Several antibiotic therapies have been proven to be effective against the multidrug resistant A. baumannii, including but not limited to: meropenem, colistin, polymyxin B, amikacin, rifampin, minocycline, and tigecycline. Monotherapy as well as combination therapies have been utilized in previous years, with varying degrees of successful treatment. As of yet, no form of therapy has been established as the most potent method of combatting the hospital-acquired infection.27,28
Despite this lack of consensus, one of the newer antibiotic therapies developed to treat Acinetobacter baumannii as well as Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae involves the use of tobramycin.29 Tobramycin is an aminoglycoside that is often utilized for treatment of strains of aerobic gram-negative bacteria, and has shown promising results in terms of empirical antibiotic treatment for AB. Furthermore, another promising aminoglycoside recently tested against AB is apramycin, a drug approved for veterinary use.30 When tested against amikacin, gentamicin, and tobramycin, apramycin displayed the lowest MIC values. Since the MIC value is essentially the lowest concentration of drug that inhibits growth of a given pathogen, this indicates that apramycin is another antimicrobial agent that must be considered a viable option for treating infections caused by A. baumannii.31
More recently, an article published in the International Journal of Antimicrobial Agents has claimed that novel antibiotic eravacycline is the most potent tetracycline class drug available to combat Acinetobacter baumannii. Researchers performed antimicrobial testing by broth microdilution of 286 non-duplicate, carbapenem-resistant AB isolates to eravacycline, amikacin colistin, doxycycline, imipenem, levofloxacin, meropenem, minocycline, sulbactam, tigecycline, and tobramycin.32 At the conclusion of the experiment, researchers determined that eravacycline exhibited the greatest potency against AB, indicating that the antimicrobial may serve as another key addition to the limited collection of drugs available to treat the harmful pathogen.
Although much of the research regarding potential treatment options for A. baumannii revolves around the use of a single antibiotic, the reality is that several options that rely on synergistic relationships between various drugs and compounds exist as well. In a relatively recent article published by the American Society for Microbiology, researchers attempted to determine whether classical β-lactamase inhibitors (BLIs) as well as could increase the efficacy of the peptide antibiotic colistin against AB.33 By combining BLI tazobactam with colistin in order to treat mice infected with the A. baumannii pneumonia, researchers were able to increase synergy that increased kill curves for 4 of 5 strains of AB tested. Since BLIs have minimal antimicrobial activity on their own, their use in combination with peptide antibiotics such as colistin warrants further study. Other experiment that have also warranted further study include Carter\’s experiment, where the combination of fosfomycin and amikacin presented 85.7% synergism on AB isolates that possessed the blaOXA-143 gene, with the bacteria\’s cell exchanging lipids with the antimicrobials, experiencing subsequent membrane disturbance and osmotic instability, and eventual apoptosis. In the same experiment, colistin sulfate or sodium colistin methanesulfonate orally administered through hematogenous transmission throughout the lungs was observed to be extremely effective, but inefficient if administered directly up through airway inoculation. Patients administering sodium colistin methanesulfonate through nebulization are advised be extremely cautious with their treatment and must inhale CMS directly after the synergistic combination has been mixed in an aqueous solution; otherwise, the CMS will be converted to colistin by hydrolysis, leaving the patient\’s lungs susceptible to bioactive noxious colistin.36
Yet the most surprising synergistic combination emerged with the conjugation of daptomycin and siderophores. Daptomycin, although not fully understood yet, has been found to land and bind on the bacterial membranes of gram-positive bacteria and disrupt their normal functions by depolarizing the ionic membrane as well as inhibit DNA replication and the production of RNA and proteins in the cells of AB.35 In an experiment conducted by Patricia A. Miller and her research team at the University of Notre Dame, the conjugation of siderophores (which are iron chelating compounds) with antibiotics much larger than it, such as daptomycin, allow the newly formed chemical compound to bypass the permeability problem it faces at the cell membrane and bind to the necessary targets that are abundant on the cell membrane of gram-positive bacteria, but not as common on the bacterial cell membranes of gram-negative bacteria.35 Because the conjugation of the iron-chelating compound with a large antibiotic requires certain recognition sites and transport proteins for the newly formed chemical compound, mutant isolates will experience no effect from the conjugated compound; however, the survival rate of such mutants were significantly lower in Miller\’s experiment, meaning that these mutants possess largely reduced fitness anyways.35
Although isolates of Acinetobacter baumannii have shown to rapidly mutate and adjust to novel antibiotic therapies, modifications to bacterial isolates have exhibited a loss in fitness and virulence. Despite the adaptation to many of these antibiotics, isolates of AB have exhibited a loss in fitness and virulence due to the genetic or posttranslational modifications that they make. The research team at the Walter Reed Army Institute of Research observed that the colistin resistant strains faced difficulty competing against non-resistant strains as at 48 hours, CR isolates were being outcompeted by their counterparts. However, the CR isolates then displayed recovery and adapted to their environment by increasing their fitness. They hypothesized that this phenomenon was due to CR isolates lacking catalases, which are essential in protecting bacteria from unstable oxygen species by breaking down hydrogen peroxide in the solution.27 It can be deduced that the period between 0 and 48 hours could be used to exploit the gram negative bacillus by covering the infected area with hydrogen peroxide and then utilizing an assortment of antibiotics and/or antimicrobials to resolve the infection. A similar conclusion was met in a study conducted by Eun-Yeong Jun and her research team at the Pasteur Institute, where overproduction of the AdeABC efflux pump system resulted in an increase to several antibiotics, but as observed before, the excess production of this efflux pump system most likely resulted in a biological cost to isolates that possess this system; therefore, based on their results, the research team postulated that the relatively low growth rate amongst these isolates stemmed from excess consumption of energy due to overactivity of these pumps or possible excretion of beneficial molecules to the bacterial isolate.34 Therefore, it is important to continue funding research to study possible loss of fitness or weaknesses that can be exploited in these type of isolates.
Ironically, enzymes created by Acinetobacter baumannii can be used to fight infections caused by the gram-negative bacteria. Bacteriophage lysins, which are present in the lytic cycle of bacteria, cleave through a multitude of bonds that exist in peptidoglycan, which are found in the cell walls of bacteria.36 Experimentation has been started and continuously regulated by Mya Thandar and her research team to synthesize a chemical compounds that possesses a molecule(s) that allow lysins to bind to the anionic bacterial cell membrane. So far, the research team has experimented with conjugating the lysins with iron-chelating compounds so the lysins can bypass the issue of cell membrane permeability. The cohort also genetically engineered a highly cationic C-terminal by supplementing the P307 amino acid sequence with eight additional amino acids(SQSRESQC), yielding P307SQ-8C; two additional modifications were made to change the amino acid sequence to P307SQ-8A. The experiment indicated that without the eight additional amino acids and the modifications, the antimicrobial peptides exhibited a reduced spectrum of activity. The hydrolyzing enzymes were active at a higher pH but not at lower salinity; the group explained this behavior the bacterial membrane losing ions in higher pH, which then resulted in the positively charged peptides to interact with anionic membrane and gain entry into the bacterial cells. The highlight of the experiment was how the lysins killed bacteria in biofilms on the surface of catheters, which limits the efficacy of the opportunistic pathogen. Further experimentation was in conjunction with the previous statement as the addition of the new amino acid sequence significantly decreased the bacterial burden in a murine skin infection.
It is imperative that the global health community design several systems of effective treatment in order to race against multi-drug resistant bacteria, including Acinetobacter baumannii. While its mechanisms of resistance are a seemingly complicated and rapidly diversifying force, the pathogenic genospecies of Acinetobacter contain the ability to rapidly mutate genes that are further resistant to common antimicrobials partially due to the antimicrobial-saturated environment (especially in healthcare facilities). Current antibiotic use generates a specific positive feedback loop, which provides AB with new sources of resistance as allowed by such mechanisms, and this overuse of these drugs must come to a close soon. New discoveries, studies, and field tests of upcoming therapeutic drugs, especially into their synergistic utilizations, should hold the greatest significance in combatting the global rise of multi-drug resistant nosocomial pathogens.
- Cunha, Burke A. \”Acinetobacter.\” Medscape. March 15, 2016. Accessed July 17, 2017. http://emedicine.medscape.com/article/236891-overview.
- Cisneros, Jose M., and Jesus Rodríguez-Baño. \”Nosocomial Bacteremia Due to Acinetobacter baumannii: Epidemiology, Clinical Features and Treatment.\” Online Wiley Library. November 13, 2002. Accessed June 29, 2017. http://onlinelibrary.wiley.com/doi/10.1046/j.1469-0691.2002.00487.x/full.
- Peleg, Anton Y., Harald Seifert, and David L. Patterson. \”Acinetobacter baumannii: Emergence of a Successful Pathogen.\” NCBI. July 21, 2008. Accessed June 30, 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2493088/.
- Qu, Junyan, Yu Du, Rujia Yu, and Xiaoju Lu. \”The First Outbreak Caused by Acinetobacter baumannii ST208 and ST195 in China.\” Hindawi. 2016. Accessed July 5, 2017. https://www.hindawi.com/journals/bmri/2016/9254907/.
- Zordan, Sabrina, Ellen Prenger-Berninghoff, Reinhard Weiss, Tanny Van Der Reijden, Peterhans Van Den Broek, George Balijer, and Lenie Djikshoorn. NBCI. September 2011, 17. Accessed July 3, 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322069/.
- Ballouz, Tala, Jad Aridi, Claude Afif, Jihad Irani, Chantal Lakis, Rakan Nasreddine, and Eid Azar. \”Risk Factors, Clinical Presentation, and Outcome of Acinetobacter baumannii Bacteremia.\” Frontiers in cellular and infection microbiology 7 (2017).
- Manchanda, Vikas, Sinha Sanchaita, and N. P. Singh. \”Multidrug resistant acinetobacter.\” Journal of global infectious diseases 2, no. 3 (2010): 291.
- Cunha, Burke A. \”Acinetobacter.\” Drugs &Diseases. January 06, 2017. Accessed August 12, 2017. http://emedicine.medscape.com/article/236891-overview.
- Kauffman, Carol. \”Acinetobacter Species.\” MDedge. August 2017. Accessed August 17, 2017. http://www.mdedge.com/emed-journal/dsm/1018/infectious-diseases/acinetobacter-species#sub1_1.
- Kim, G., B. Oh, J. S. Song, P. G. Choe, W. B. Park, H. B. Kim, N. J. Kim, E. C. Kim, and M. D. Oh. \”O047: The effect of active surveillance culture of carbapenem resistant Acinetobacter baumannii on the occurrence of carbapenem resistant Acinetobacter baumannii bacteremia in a single intensive care unit.\” Antimicrobial Resistance and Infection Control 2, no. 1 (2013): O47.
- Ninin, Emmanuelle, Franchise Nicolas, and Herve Richet. \”Nosocomial Acinetobacter baumannii infections: microbiological and clinical epidemiology.\” Ann Intern Med 129 (1998): 182-189.
- Agodi, Antonella, Martina Barchitta, Annalisa Quattrocchi, Andrea Maugeri, Eugenia Aldisio, Anna Elisa Marchese, Anna Rita Mattaliano, and Athanassios Tsakris. \”Antibiotic trends of Klebsiella pneumoniae and Acinetobacter baumannii resistance indicators in an intensive care unit of Southern Italy, 2008–2013.\” Antimicrobial resistance and infection control 4, no. 1 (2015): 43.
- Ning, Nian-zhi, Xiong Liu, Chun-mei Bao, Su-ming Chen, En-bo Cui, Jie Huang, Fang-hong Chen, Tao Li, Fen Qu, and Hui Wang. \”Molecular epidemiology of bla OXA-23-producing carbapenem-resistant Acinetobacter baumannii in a single institution over a 65-month period in north China.\” BMC infectious diseases 17, no. 1 (2017): 14.
- Fournier, Pierre Edouard, Hervé Richet, and Robert A. Weinstein. \”The epidemiology and control of Acinetobacter baumannii in health care facilities.\” Clinical infectious diseases 42, no. 5 (2006): 692-699.
- Munier, Anne-Lise, Lucie Biard, Clotilde Rousseau, Matthieu Legrand, Matthieu Lafaurie, Alexandra Lomont, Jean-Luc Donay et al. \”Incidence, risk factors and outcome of multi-drug resistant Acinetobacter baumannii acquisition during an outbreak in a burns unit.\” Journal of Hospital Infection (2017).
- Berlau, J., H. Aucken, H. Malnick, and T. Pitt. \”Distribution of Acinetobacter species on skin of healthy humans.\” European Journal of Clinical Microbiology & Infectious Diseases 18, no. 3 (1999): 179-183.
- Mustikawati, B. Indah, N. Syitharini, S. Widyaningtyastuti, and L. Gunawan. \”Implementation of WHO multimodal hand hygiene (HH) improvement strategy to reduce healthcare-associated infections (HAI) and VAP (ventilator-associated pneumonia) caused by multi-drug resistant Acinetobacter baumanii (MDRAB) at Siloam Hospitals Surabaya (SHBS), Indonesia.\” Antimicrobial Resistance and Infection Control 4, no. 1 (2015): O18.
- Madaan, A., V. Singh, P. Shastri, and C. Sharma. \”Comparison of multidrug-resistant Acinetobacter and non-Acinetobacter infections in terms of outcome in critically ill patients.\” Critical Care 18, no. 1 (2014): P351.
- Coyne, Sébastien, Patrice Courvalin, and Bruno Périchon. \”Efflux-Mediated Antibiotic Resistance in Acinetobacter.\” Antimicrobial Agents and Chemotherapy. December 20, 2010. Accessed July 20, 2017. http://aac.asm.org/content/55/3/947.full.
- Sun, Jingling, Ziqing Deng, and Alxin Yan. \”Bacterial Multidrug Efflux Pumps: Mechanisms, Physiology and Pharmacological Exploitations.\” Science Direct. September 2015. Accessed July 17, 2017. http://www.sciencedirect.com/science/article/pii/S0006291X14009711.
- Hassan, Karl A., Qi Liu, Peter J.F. Henderson, and Ian T. Paulsen. \”Baumannii AceI Transporter Represent a New Family of Bacterial Multidrug Efflux Systems.\” MBIO. February 15, 2015. Accessed August 1, 2017. http://mbio.asm.org/content/6/1/e01982-14.full#ref-1.
- Leite, Gleice Cristina, Maura S. Oliveira, Laura Viera Perdigão-Neto, Cristiana Kamia Dias Rocha, Thais Guimarães, Camila Rizek, Anna Sara Levin, and Silvia F. Costa. \”Antimicrobial Combinations against Pan-Resistant Acinetobacter baumannii Isolates with Different Resistance Mechanisms.\” Plos. March 21, 2016. Accessed July 17, 2017. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151270.
- Moffatt, Jennifer H., Marina Harper, Paul Harrison, John D.F. Hale, Evgeny Vinogradov, Torsten Seemann, Rebekah Henry, Bethany Crane, Frank St. Michael, Andrew D. Cox, Ben Adler, Roger L. Nation, Jian Li, and John D. Boyce. \”Colistin Resistance in Acinetobacter baumannii Is Mediated by Complete Loss of Lipopolysaccharide Production ▿.\” Antimicrobial Agents and Chemotherapy. September 10, 2010. Accessed July 10, 2017. http://aac.asm.org/content/54/12/4971.full.
- Jones, Crystal L., Shweta S. Singh, Yonas Alamneh, Leila G. Casella, Robert K. Ernst, Emil P. Lesho, Paige E. Waterman, and Daniel V. Zurawski. \”In Vivo Fitness Adaptations of Colistin-Resistant Acinetobacter baumannii Isolates to Oxidative Stress.\”
- Trebosc, Vincent, Sarah Gartenmann, Kevin Royett, Pablo Manfredi, Marcus Totzl, Birgit Schellhorn, Michael Pierren, Marcel Tigges, Sergio Lociuro, Peter C. Sennhen, Marc Gitzinger, Dirk Bumann, and Christian Kemmer. \”A Novel Genome-Editing Platform for Drug-Resistant Acinetobacter baumannii Reveals an AdeR-Unrelated Tigecycline Resistance Mechanism.\” Antimicrobial Agents and Chemotherapy. September 26, 2016. Accessed July 15, 2017. http://aac.asm.org/content/60/12/7263.full.
- Carter, Andrew P., William M. Clemmons, Ditlev E. Broderson, Robert J. Morgan-Warren, Brian T. Wimberly, and V. Ramakrishna. \”Functional Insights from the Structure of the 30S Ribosomal Subunit and its Interactions with Antibiotics.\” Nature: International Weekly Journal of Science. August 10, 2000. Accessed July 19, 2017. http://www.nature.com/nature/journal/v407/n6802/abs/407340a0.html?foxtrotcallback=true.
- Cunha, Burke A. \”Pharmacokinetic Considerations Regarding Tigecycline for Multidrug-resistant (MDR) Klebsiella Mneumoniae or MDR Acinetobacter baumannii Urosepsis.\” Journal of Clinical Microbiology 47, no. 5 (2009): 1613-1613.
- Garnacho-Montero, J., C. Ortiz-Leyba, F. J. Jimenez-Jimenez, A. E. Barrero-Almodovar, J. L. Garcia-Garmendia, M. Bernabeu-Wittell, S. L. Gallego-Lara, and J. Madrazo-Osuna. \”Treatment of Multidrug-Resistant Acinetobacter baumannii Ventilator-associated Pneumonia (VAP) with Intravenous Colistin: A Comparison with Imipenem-susceptible VAP.\” Clinical Infectious Diseases 36, no. 9 (2003): 1111-1118.
- Schafer, Andrew I., and Lee Goldman. Goldman-Cecil Medicine. Elsevier Health Sciences, 2016.
- Kang, Anthony D., Kenneth P. Smith, George M. Eliopoulos, Anders H. Berg, Christopher McCoy, and James E. Kirby. \”Invitro Apramycin Activity Against Multidrug-resistant Acinetobacter Baumannii and Pseudomonas Aeruginosa.\” Diagnostic Microbiology and Infectious Disease 88, no. 2 (2017): 188-191.
- Matros, Linda, and Terri Wheeler. \”Microbiology Guide to Interpreting MIC (Minimum Inhibitory Concentration).\” The Vet. February 2001. Accessed August 11, 2017. http://www.the-vet.net/DVMWiz/Vetlibrary/Lab-%20Microbiology%20Guide%20to%20Interpreting%20MIC.htm.
- Seifert, Harald, Danuta Stefanik, Joyce A. Sutcliffe, and Paul G. Higgins. \”In-vitro Activity of the Novel Fluorocycline Eravacycline Against Carbapenem Non-susceptible Acinetobacter baumannii.\” International Journal of Antimicrobial Agents (2017).
- Sakoulas, George, Warren Rose, Andrew Berti, Joshua Olson, Jason Munguia, Poochit Nonejuie, Eleanna Sakoulas, Michael J. Rybak, Joseph Pogliano, and Victor Nizet. \”Classical β-lactamase Inhibitors Potentiate the Activity of Daptomycin Against Methicillin-resistant Staphylococcus Aureus and Colistin against Acinetobacter baumannii.\” Antimicrobial Agents and Chemotherapy 61, no. 2 (2017): e01745-16.
- Yoon, Eun-Jeong, Vivianne Balloy, Laurence Fiette, Michel Chignard, Patrice Courvalin, and Catherine Grillot-Courvalin. \”Contribution of the Ade Resistance-Nodulation-Cell Division-Type Efflux Pumps to Fitness and Pathogenesis of Acinetobacter baumannii.\” American Society for Microbiology. May 31, 2016. Accessed August 14, 2017. http://mbio.asm.org/content/7/3/e00697-16.full.
- Ghosh, Manuka, Patricia A. Miller, Ute Möllmann, William D. Claypool, Valerie A. Schroeder, William R. Wolter, Mark Suckow, Honglin Yu, Shuang Li, Weiqiang Huang, Jaroslav Zajicek, and Marvin J. Miller. \”Targeted Antibiotic Delivery: Selective Siderophore Conjugation with Daptomycin Confers Potent Activity against Multidrug Resistant Acinetobacter baumannii Both in Vitro and in Vivo.\” Journal of Medicinal Chemistry. March 13, 2017. Accessed August 15, 2017. http://pubs.acs.org/doi/full/10.1021/acs.jmedchem.7b00102.
Thandar, Mya , Rolf Lood, Benjamin Y. Winer, Douglas R. Deutsch, Chad W. Euler, and Vincent A. Fischetti. \”Novel Engineered Peptides of a Phage Lysin as Effective Antimicrobials Against Multidrug-Resistant Acinetobacter baumannii.\” Antimicrobial Agents and Chemotherapy. February 8, 2016. Accessed August 16, 2017. http://aac.asm.org/content/60/5/2671.full.
About the Authors
Devansh J. Kurup is a high school senior at Independence High School in Frisco, Texas. He is exploring his scientific curiosity by co-authoring this review article on the nosocomial pathogen Acinetobacter baumannii. He is currently training to become a certified Pharmaceutical Technician in the near future. Moreover, he has logged over 60 hours serving in clinical facilities in the Dallas-Fort Worth.
Owais Fazal is a Certified Nursing Assistant (CNA) from Houston, TX. He currently attends Rice University and is majoring in Social Policy Analysis and Global Health Technologies. He has researched several aspects of the field of public health, including epidemiology, biostatistics, serology, vaccine development, clinical manifestations, and preventive measures for the spread of infectious diseases. He has published a review article titled “A pandemic in disguise: Zika virus vaccine development and counteractive measures analysis” in the Saudi-based Journal of Health Specialties. Furthermore, he has logged over 500 clinical hours in medical facilities throughout the Dallas-Fort Worth metroplex and has shadowed physicians in the fields of cardiology, neurology, and oncology. In terms of laboratory experience, he has completed over 40 hours conducting research in the field of psychology. He currently looks forward to becoming involved in cancer research at M.D. Anderson alongside cutting edge researchers from across the globe. Moreover, he is currently in the process of learning Spanish and hopes to study abroad in Latin America, working with local public health officials to educate regional populations regarding the principles of infectious disease prevention. Finally, he hopes to pursue a joint M.D./M.P.H. program at the University of Pennsylvania.
Taha Hassan is a senior at Independence High School in Frisco, Texas. He is making his debut into the world of medical journals by co-authoring this one on the nosocomial pathogen Acinetobacter baumannii. He is currently working at the IACC Psychiatric Clinic at his local mosque in Plano, Texas, where is an active nonprofit worker that. He currently looks forward becoming a world class neurosurgeon and help explore the brain with ground breaking discoveries. He also has aspirations to delve into the world of AI and become involved in the process of creating artificial intelligence will one day be ubiquitous throughout society. Moreover, he is currently competing in academic competitions such as Health Occupations Students of America, Academic Decathlon, and Business Professionals of America, where he hopes to stand out and secure some medals. In his spare time, he spends time with his hyperactive 3 younger brothers, wrestling and indulging in all sorts of sports with them. He wishes to attend Rice University and begin conducting laboratory research pertaining to neuroscience. In his postgraduate studies, he hopes to pursue a dual M.D./M.P.H. program at the prestigious institute of Stanford University, where he can also partner with upcoming tech startups and assist in developing more advanced forms of artificial intelligence.