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Home , Acinetobacter baumannii, Acinetobacter parvus, Acinetobacter schindleri, Acinetobacter ursingii

Central European Journal of Clinical Research Volume 2, Issue 1, Pages 28-36 DOI: 10.2478/cejcr-2019-0005

REVIEW

Evolution of baumannii infections and . A review

Sonia Elena Popovici1, Ovidiu Horea Bedreag2, Dorel Sandesc2 1“Pius Branzeu” Emergency County Hospital, Timisoara, Romania 2 Faculty of Medicine, “Victor Babes” Univeristy of Medicine and Pharmacy, Timisoara, Romania

Correspondence to: Sonia Elena Popovici, MD Clinic of Anesthesia and Intensive Care “Pius Branzeu” Emergency County Hospital, Timisoara, Romania, Bulevardul Liviu Rebreanu, Nr. 156, Cod 300723, Timișoara E-mail: [email protected]

Conflicts of interests Nothing to declare

Acknowledgment None

Funding: This research did not receive any specific grant from funding agencies in the public, commercial or not-for profit sectors.

Keywords: Acinetobacter baumannii, hospital-acquired, antimicrobial resistance.

These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Central Eur J Clin Res 2019;2(1):28-36 ______Received: 12.12.2018, Accepted: 15.01.2019, Published: 25.03.2019

Copyright © 2018 Central European Journal of Clinical Research. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. in the hospital environment and the multitude of transmission possibilities raises serious issues Abstract regarding the management of these complex in- fections. The future lies in developing new and The emergence of multi-drug resistant targeted methods for the early diagnosis of A. Acinetobacter spp involved in hospital-acquired baumannii, as well as in the judicious use of an- infections, once considered an easily treatable timicrobial drugs. This review details the evolu- pathogen, is troublesome and an immense bur- tion of the pathogenicity of this microorganism, den for the modern medical systems worldwide. together with the changes that appeared in re- In the last 20 years the medical community re- sistance mechanisms and the advancements in corded an increase in the incidence and severi- molecular testing for the early detection of in- ty of these infections as therapeutic means tend fection. to be less and less effective on these strains. The ability of these to rapidly develop Introduction resistance to antimicrobial agents by continu- ously changing and adapting their mechanisms, The critically ill patient as one of the big- their ability to survive for long periods of time gest challenges in the medical world has a con- 28 Evolution of Acinetobacter baumannii antimicrobial resistance. A review stant need of complex management which also fections have been reported, especially in the involves the prevention and treatment of asso- case of hospital-acquired infections, raising a ciated infections. The length of stay in the ICU, red flag related to the lack of therapeutic means the mechanical ventilation time, the invasive for the ever-evolving multidrug-resistant strains techniques used, as well as the nutrition strate- of this bacterium. Together with technologi- gy all make the critically ill patient susceptible to cal advancements, in 1986 four new genomic infection and influence the clinical outcome and species were proposed after using DNA-DNA mortality rates. It was proven that the mortality hybridization: 3TU, 13 TU, Acinetobacter bau- risk is 2.48 times higher in critically ill patients mannii, and Acinetobacter calcoaceticus which with hospital-acquired infections especially in together form the “A. baumannii complex” [4], as the case of patients with respiratory disease [1]. they share common properties that make them Bacterial infections are a heavy burden hard to distinguish from each other. A. bauman- on the medical systems and on patients world- nii infections associated with medical interven- wide, with the most threatening being patho- tions were proven to have high- which gens of the respiratory tract, enteric pathogens altered the belief that it was a low-virulence and HIV-associated infections. Finding new pathogen acting as an opportunist [5]. Their treatment options represents a constant chal- potential of rapidly developing resistance to lenge for the medical community, as the fight is antimicrobial agents, their capacity of surviving against the continuously evolving mechanisms in the hospital environment for long periods of of microbial resistance. New hope comes from time, and the numerous transmission mecha- the recent advances in the field of genetics, nisms have raised serious issues worldwide mainly DNA sequencing that offer the possibility regarding the treatment and management of of comparing the genomes of the same strains hospital-acquired Acinetobacter spp. infections over a period of time in order to identify genetic [6]. Wright et al. carried out a genomic analysis changes signifying the development of adapta- of A. baumannii isolated from the same patient tion techniques of the microorganism to certain during their hospital stay and have proven that drugs or to the environment [2]. Along the years treatment and host response led to research groups have struggled to elucidate the enrichment in mutation [7]. resistance mechanisms of certain pathogens involved in acute infections, such as Neisseria Microbiology – current classification meningitidis, , and and relevance in the clinical setting Acinetobacter baumannii, with a soft focus on their genomic evolution. The genus Acinetobacter encompass- es opportunistic pathogens, gram-negative Background coco-bacilli in pairs, with dimensions between 1 and 1.5 μm that do not present mobility, and The alarming increase in the incidence produce a catalase enzyme (catalase-positive) of infections determined by opportunistic micro- but does not produce cytochrome oxidase (ox- organisms, especially as epidemiologic events idase-negative) or urease. Regarding nutrition- such as nosocomial infections, have deter- al mechanisms these pathogens are aerobic, mined researchers in the fields of microbiology non-fermenting, and non-fastidious [8]. More re- and molecular biology to carry out studies on cent classification strategies have proposed to these certain types of pathogens. Acinetobacter classify the genus Acinetobacter as part of the baumannii is an ubiquitary bacterium that col- family and of the more extensive onizes over 40% of healthy adults that come class. into contact, with a higher incidence seen in the The A. baumannii complex includes the medical personnel. three most clinically important species that have Belonging to a wider class called Gam- been involved in community-acquired and hos- maproteobacteriae, germs in the Acinetobacter pital-acquired infections in humans, as well as a genus have long been considered as opportun- fourth specie, A. calcoaceticus, frequently found ists, usually involved in less severe infections. in water and that does not inflict diseases in Genus Acinetobacter as we nowadays call it the human population. Apart from the “Acineto- was first discovered in 1911 by Martinus Bei- bacter complex” Bouvet and Grimont, and lat- gerinck, as a gram-negative bacterium [3]. Only er Bouvet and Jeanjean [4], described further in 1970 was this pathogen recognized as being genospecies through DNA-hybridization includ- significantly involved in hospital infections, but ing: A. haemolyticus, A. johnosnii, A. junii, A. with a high sensitivity to common antimicrobials Iwoffii, and A. radioresistens. In the last two de- used at the time. However, in the last 30 years cades additional species have been identified, an increased incidence and severity of the in- but out of the total 10 only 3 are of human origin:

29 Evolution of Acinetobacter baumannii antimicrobial resistance. A review A. parvus, A. schindleri, and A.ursingii [9,10,11]. sence of specific structures in the chromosomal Up until now the following species of the Acine- or extra-chromosomal DNA sequence. Natural tobacter genus have been identified, with their variability does not influence these methods type and reference strains mentioned in the as much but they can be affected by insertion, brackets: A. baumannii (ATCC19606T) – with deletions, and point mutations. Fortunately the two genomic species, A.baylyi (DSM14961T), incidence of these defects is lower, and in many A. bouvetii (DSM 14961T), A. calcoaceticus cases they can represent diagnostic or epidemi- (ATCC 23055T) - one genomic specie, A. gern- ologic biomarkers. eri (DSM 14967T), A. grimontii (DSM 14968T), A. baumannii species present indige- A. haemolyticus (ATCC 17906T) with 4 genomic nous plasmids and therefore plasmid analysis species, A. johnsonii (ATCC 17909T) with 7 ge- is one method that has been used for the epi- nomic species, A. junii (ATCC 17908T) with 5 demiological typing but only after taking into ac- genomic species, A. lowffii(ACTC 15309, ATCC count that plasmids can be gained or lost in the 9957) with 8, respectively 9 genomic species, transformation process [16]. A. parvus (NPH384T), A. radioresistens (IAM Ribotyping, although labor-intensive 13186T) with 12 genomic species, A. schin- and with limited discriminatory power, has been dleri (NIPH1034T), A. tandoii (DSM 14970T), used to identify species of Acinetobacter. The A. tjernbergiae (DSM 14971T), A. twoneri (DSM method applied in the past in epidemiolog- 14962T), A. ursingii (NIPH137T), A. venetianus ic studies uses EcoRI, ClaI, and SalI in order (ATCC 31012, ATCC 19004, 10090 – close to to obtain the restriction of DNA; after this step 13TU) [4,9,12,13,14] electrophoresis must be carried out, followed by blotting and hybridization with a probe de- Identification ofAcinetobacter strains rived from E.Coli ribosomal RNA [9]. Because the technique is both expensive and time-con- For the identification of Acinetobacter suming, and requires specific equipment it was strains one must use a combination of pheno- replaced by pulse-field gel electrophoresis typic and genotypic tests that must be charac- (PFGE). terized by high reproducibility, good discrimina- Pulse-field gel electrophoresis (PFGE) tion strength, and that are easily carried out and remains the gold standard for identifying Acine- easy to interpret [15]. Samples in the case of tobacter baumannii [9]. It is a so-called compar- ICU patients can be collected from different sites ative typing system as it uses ApaI to impose such as: lower respiratory tract secretions, urine, restriction on chromosomal DNA [17], followed wound secretion, central lines, or even skin. by electrophoresis for the separation of these Along the years this species has become more fragments and by the comparison of the finger- and more aggressive, as well as more resistant print profiles. Reproducibility between different to even the most modern therapies. There are laboratories is also possible which would help different methods for testing but unfortunately in the detection of epidemic strains in a certain standard techniques used in the laboratory will hospital or even nation-wide [18]. only identify the genus and not the species [14]. Applied fragment length polymorphism Phenotypic identification methods such as the analysis (AFLP analysis) is a semiautomated biochemical profile, phagocytic typology, sur- procedure and a powerful tool in determining face antigens profile, antibiotic susceptibility in bacterial strains, but being a meth- etc. represent the expression of certain genetic od that requires high level equipment and stan- structures, and therefore are susceptible to vari- dardization it is found in reference laboratories ability due to the influence of the culture envi- and it is not used in the daily practice for routine ronment , bacterial growth phase, spontaneous analysis of A. baumannii [19]. mutations [14]. Among the most used biotyping The sequence analysis for 16S rDNA methods one of the most widely used in the clin- genes and rpoB genes are molecular identifi- ical setting is the API 20NE and API 20E (Bio- cation methods that are widely accepted, as Merieux, France) test. Complementary growth well as the PCR-RFLP molecular technique. at 44 °C is sometimes required although the test PCR Amplification of blaOXA-51 and CHROMagar has high reliability [15]. Acinetobacter/MDR Technique are other tests that together with the antimicrobial susceptibil- Molecular techniques ity testing can aid in a correct and goal directed therapy for A. baumannii infections [20].DNA Genetic methods analyze the microor- extraction is another option, as well as PCR re- ganism’s genetic structure and include the poly- actions. morphism of the enzymatic restriction patterns As all gram-negative bacteria, the of the total DNA, as well as the presence or ab- Acinetobacter species expresses lipopolysac-

30 Evolution of Acinetobacter baumannii antimicrobial resistance. A review charides (LPSs), present on the outer surface guished biochemically [27]. This pathogen is of the microorganism [21], that were shown to able to infect and survive on hospital surfaces be of smooth phenotype after serological and for long periods of time and therefore lead to chemical analysis [22-24]. Monoclonal antibod- hospital-acquired infections in susceptible pa- ies (MAbs) against the LPSs of the A. bauman- tients and nosocomial outbreaks [8,28]. The nii strains were generated; MAb S48-3-13 and vast majority of clinically relevant infections MAb S48-3-17 were found to react with certain appear in hosts with a compromised immune strains [12]. Another pair of mouse monoclonal system, where the virulence factors allow col- antibodies used against A. baumannii ATCC onization and infection. Among these virulence 19606 was reported by Baig et al [25], mainly factors we mention: production and release of F241G3sc2 and F241G6sc2 that have proven exopolysaccharides, the LPS that can contrib- to be highly sensitive and demonstrated appli- ute to its pathogenicity through their mutagenic cability in the clinical practice by use of ELISA properties and their ability to induce TNF-alpha testing and Western Blot analysis, and therefore synthesis [29]. Mortality rates in hospitalized can be used as rapid detection tools [25]. More- patients infected with this pathogen reach 26%, over, in the last years, humanized MAbs have while mortality in the ICU patient group reaches emerged as possible effective treatment options 43% [30]. or prevention options for A. baumannii infec- Acinetobacter baumannii has been iso- tions, especially with multi-drug resistant (MDR) lated from all culture sites, but the most com- or extensive-drug resistant (XDR) strains. mon infection and colonization site remains the Another very important part is deter- inferior respiratory tract. It is the main pathogen mining the sensitivity/resistance profile to anti- incriminated in ventilator-associated pneumonia microbial drugs. This test can be applied to all (VAP) but lately it has been proven that it can strains and is easy to perform and interpret. The also lead to community-acquired pneumonia laboratory clinician will determine either the in- in patients that present with further risk factors hibition area, or the minimum inhibitory concen- such as COPD, alcoholism, heavy smoking, tration (MIC). The resistance profile is very vari- and diabetes, with a high prevalence in Asia as able and can rapidly change in the same patient well as [31]. Among the risk factors for or in the same epidemiologic outburst. Another developing an infection with A. baumannii Arod- example of molecular and biochemical methods ino et al. [32] mentioned bronchoscopy and ox- that are useful in the detection of antimicrobial ygen therapy as invasive procedure performed resistance profiles is the detection of carbapen- outside the ICU or before the admission in the emase-producing Acinetobacter baumannii, as ICU, together with obesity or malnutrition, se- these strains have developed and evolved on vere liver disease, and the type and duration of a fast-raging pace over the last years. Two of antibiotic therapy. Apart from respiratory infec- these methods were described by Thoma et. al, tions cause by A. baumannii, other types and CarbaAcinetoNP and BlueCarba Test, togeth- localizations of infections are also possible such er with PCR testing for carbapenemases [26]. as , bloodstream and central-line as- Testing the ability of producing large-spectrum sociated, skin or wound. betalactamases (BLSE) can also be achieved, A. baumannii also has a horizontal through the double-disc method. Genotyping transmission pattern, from one patient to the methods for MDR A. baumannii include: am- other when they are hospitalized in close vicin- plified fragment length polymorphism analysis ity and it is also capable of colonizing surfaces (AFLP), PFGE, multiple locus variable num- which apart from hospital furniture can also refer ber tandem repeat analysis (MLVA), single lo- to feeding tubes. Wrong manipulation and lack cus genotyping, resistance island typing, and of hygiene will therefore lead to the spread of next-generation whole-genome sequencing the infection. In the ICU wards the main source (NG WGS) with each having different genetic for the infection are catheters of all types, equip- targets and specific features. ment used for mechanical ventilation and other type of ventilatory support, and suction devices Pathogenicity and pathogenesis of [9]. Acinetobacter spp The pulmonary colonization and infec- tion begins through the adherence to host cells The species of the Acinetobacter genre that can be followed by the formation of a bio- can be involved in hospital-acquired infections, film, dependent on the existence of pilli on the the most commonly identified in the clinical set- bacterial outer membrane. A. baumannii forms ting being A. baumannii, more specifically the on both biotic and abiotic surfaces genospecies included in the “Acinetobacter which makes the microorganism metabolically baumannii complex”, that cannot be distin- inert. It is because of this mechanism that vir-

31 Evolution of Acinetobacter baumannii antimicrobial resistance. A review ulence is increased as cannot pene- that would eradicate infections from the face of trate or act on metabolically inert organisms [8]. the Earth, not knowing the capability of bacte- production is deeply influenced by other ria of counteracting this fight. The first penicil- virulence factors such as the family of BAP pro- lin-resistant microorganisms have been report- teins (biofilm associated ), OmpA, and ed only one year after the first administration BAP-like [33]. of , and methicillin soon followed the Ab0mpA (outer membrane protein) is same pattern. With regard to A. baumannii up a major membrane protein that is highly immu- until 1970 infections were easily treatable but nogenic and leads to an increase expression of high rates of resistance emerged as early as cytochrome c which is a proapoptotic molecule. 1975. In the late years many valuable drugs are High concentrations of Ab0mpA induce apop- no longer efficient in the treatment of these in- tosis of dendritic and epithelial cells that leads fections, including cephalosporins, , to the destruction of the mucosa and allows the most and cefoxitin [9,38]. The bacteria to penetrate deeper tissues [34]. In low current therapeutic regimens include carbap- concentrations Ab0mpA stimulates the expres- enems, although recent studies have shown sion of CD80, CD86, CD40, Major Histocompat- increased resistance, fluroquinolones, and ibility Complex (MHC) class I, and MHC class II, sometimes broad-spectrum chephalosporines if as well as the production of interleukin 1 (IL1); it the microorganism is susceptible. Even in sus- also determines epithelial cells to become more ceptible strains in the late years MICs have in- responsive to ligands by increasing the surface creased [39]. Based on their research Marvig et expression of Toll-Like Receptor 2(TLR 2) which al., concluded that the population of A. bauman- plays an important role in the pulmonary host nii includes at least nine distinct clonal lineages defense mechanism. The membrane LPS of A. worldwide [40]. baumannii has been proven to be involved in In their study, Hua et al. [41] carried out the pathogenesis of by inducing pro-in- the analysis of 172 genomes of isolated A. bau- flammatory cytokine synthesis and by binding to mannii, from 86 different patients to research CD14 and the TLR4/MD-2 complex [35]. the evolution of the microorganism within its Neutrophil depression significantly re- host and they have shown that worldwide A. duces the cytokine levels showing that these baumannii comprises of three major internation- cells play a crucial role in the pro-inflammatory al lineages: EC I, EC II, and EC III. Out of the response of the lung. Recruiting a high number three the dominant one is EC II with its subgroup of neutrophils in the upper and lower airway ICL-II that represents the -resistant and in the lung parenchyma was correlated A. baumannii. After analyzing the single nucleo- with the eradication of A. baumannii infection tide polymorphism (SNPs) for within-patient di- in the lungs [36]. Macrophages on the other versity they have shown that over 15 genes has hand are the first defense line and involved in been mutated more than one time. A gene with the phagocytosis in the lower airways. They ex- a significant role in capsule synthesis, ptk has press a variety of cellular recognition molecules been shown to be mutated the most, with the and studies have proven that they have a direct mutant microorganism presenting higher motil- role in the local defense against A. baumannii ity levels. Another mutation was that of adeRS through a NO-dependent mechanism that need that increased the resistance to . Hua an intact and functional microfilament and mi- et al have also shown that A. baumannii is re- crotubule system in order to function adequately sistant to major antimicrobial drugs and that the [37]. Understanding the virulence mechanisms resistance increases together with its evolution of A. baumannii can facilitate the development within the host [41]. of new immunotherapies, as well as new anti- Since the 1980s the spread of A. bau- biotics. mannii infections has been a problem across Europe, with outbreaks in hospitals in western Mechanisms of antimicrobial European countries such as , the Neth- resistance and their evolution pattern erlands, France and Italy [42]. After identifying the epidemic strains infecting these hospitals it From once being only an opportunistic was proven that transmission is also possible bacterium, easy to treat even with narrow-spec- between hospitals, most probably via trans- trum antibiotics A. baumannii has evolved to fers of infected or colonized patients [43]. The being capable of mutations associated both possibility of spread of multi- A. with antimicrobial therapies and with the host baumannii is possible not only from a patient to response. Since 1928, with the great discovery the other or from one hospital to the other, but of Alexander Fleming – Penicillin – people have also at a national and even international level, thought that they discovered a “magic weapon” a fact that was proven by many different stud-

32 Evolution of Acinetobacter baumannii antimicrobial resistance. A review ies. Turton et al have described the multi-hos- [52]. This class of antimicrobials exerts their ac- pital epidemic given by the “Southeast clone” tivity through the inhibition of protein synthesis. and by the Oxa-23, Oxa-1, and Oxa-2 clones This is achieved by binding to the ribosomal (all MDR-A. baumannii) which infected patients RNA (16S) of the ribosomal subunit (30S) but A. in English hospitals and disseminated through baumannii is capable of producing ArmA which Southeast England [44]. Another example is the is a 16S ribosomal RNA methyltransferase [9], epidemic that affected northern and southeast- protecting the -binding site from ern France, where a VEB-1 ESBL A. bauman- binding the drug [53]. nii clone spread in a total of 55 medical centers is an antimicrobial with bacteri- [45]. Moreover, hospital outbreaks in Northern cidal activity and exerts its effect by binding to Europe, Eastern Europe and other EU coun- lipid A, an endotoxin of gram-negative bacteria, tries such as Greece and Spain were reported and the interior layer of the LPS. Modification with three international clones of A. baumannii, of lipid A lead to resistance to colistin, by the mainly the European clone I, II, and III. Epidemi- addition of phosphoetanolamine [56]. Another ologists and researchers could not find the link mechanism that renders colisitin ineffective is between the outbreaks given by these Europe- the total loos of the LPS [57]. an clones [46]. A. baumannii also presents both mod- The resistance mechanisms to Cepha- erate and high-level resistance to fluorochinolo- losporins in the case of A. baumannii is given nes. As a mechanism of action they bind to the by the natural production of Acinetobacter-de- topoisomerase IV and DNA gyrase [9], therefore rived cephalosporinase (also called AmpC disrupting the synthesis of DNA and inducing β-lactamase or, shorter, ADC). In this case the cell death. The microorganism substitutes ami- production of ADC cannot be repressed, and no acids in the genes that encode target pro- what makes it even more dangerous is the fact teins for the quinolone resistance determining that it can even be enhanced by the insertion region [54], this leading to high levels of resis- of certain sequences in the gene which in the tance to fluorochinolones. Moderate levels of end leads to a high level of resistance [47, 48]. resistance are achieved by the overexpression Certain strains of A. baumannii also have the of active pumps [55,9]. capacity of producing, apart from ADC, the ex- tended-spectrum β-lactamase (ESBL) which Conclusions also renders them resistant to cephalosporins [49]. The emergence of multi-drug resistant On the other hand, the production of Acinetobacter spp involved in hospital-acquired carbapenemases is the most important mech- infections is troublesome and an immense bur- anism for resistance of A. baumannii to carbap- den for the modern medical systems worldwide, enems. Carbapenemases can be produced by especially because of the ever-developing the microorganism naturally, such as the group strains capable of ESBL and carbapenemases of OXA-51 chromosomally encoded carbapen- production that led to pan-resistance (exten- emases, but they can also be acquired. In the sive resistance to , aztreonam, same manner as for the ADS, resistance can all cephalosporins, aminoglycosides, and flu- be reinforced through an insertion sequence orochinolones). These strains have a high po- upstream of OXA-51 gene which will lead to tential of survival for long periods of time in the increased MICs for carbapenems [9,50]. In the hospital environment, leading to contamination recent years A. baumannii has acquired carbap- of medical equipment and prosthetic devices. enemases in the non-OXA group, that up until The risk factors for hospital-acquired recently were specific for the Enterobacteriace- infections with multi-drug resistant A. bauman- ae. nii include admission in the intensive care unit, Sulbactam, which used to be a solution mechanical ventilation, invasive procedure and for the β-lactamase producing group, is given as surgical interventions, using prosthetic devices, a combination with either ampicillin or cefaper- as well as previous antibiotic treatment with car- azone, but it also has its own activity against bapenems, 3rd generation cephalosporins, and A. baumannii. However, in the last decades quinolones. through the production of TEM-1 β-lactamase Modern testing for A. baumannii strains and through low expression of penicillin-binding and for the resistance profiles should be avail- pretin (PBP2), A. baumannii has managed to able to all healthcare authorities. However, ge- develop resistance to this drug [51,9]. netic testing is still not accessible everywhere, The activity of aminoglycosides is af- but with future reduction of costs for the DNA fected by the ability of the bacteria to produce library preparation could make genomics a tool a variety of aminoglycoside-modifying enzymes that could be used for routine surveillance [2].

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