Acinetobacter baumannii: An emerging pathogenic threat to public health

Abstract

Over the last three decades, Acinetobacter has gained importance as a leading nosocomial pathogen, partly due to its impressive genetic capabilities to acquire resistance and partly due to high selective pressure, especially in critical care units. This low-virulence organism has turned into a multidrug resistant pathogen and now alarming healthcare providers worldwide. Acinetobacter baumannii (A. baumannii) is a major species, contributing about 80% of all Acinetobacter hospital-acquired infections. It disseminates antibiotic resistance by virtue of its extraordinary ability to accept or donate resistance plasmids. The procedures for breaking the route of transmission are still proper hand washing and personal hygiene (both the patient and the healthcare professional), reducing patient’s biofilm burden from skin, and judicious use of antimicrobial agents. The increasing incidence of extended-spectrum beta-lactamases and carbapenemases in A. baumannii leaves almost no cure for these “bad bugs”. To control hospital outbreaks of multidrug resistant-Acinetobacter infection, we need to contain their dissemination or require new drugs or a rational combination therapy. The optimal treatment for multidrug-resistant A. baumannii infection has not been clearly established, and empirical therapy continues to require knowledge of susceptibility patterns of isolates from one’s own institution. This review mainly focused on general features and introduction to A. baumannii and its epidemiological status, potential sources of infection, risk factors, and strategies to control infection to minimize spread.

Key Words: Acinetobacter, Acinetobacter baumannii, Biofilm, Combination therapy, Hospital-acquired infection, Intensive care unit, Multidrug resistance, Nosocomial Pathogen, Risk factor

Core tip:Acinetobacter, is Gram-negative cocco-bacilli, originally regarded as low virulence bacteria, adopted now with increasing incidences, and recognized as a significant healthcare-associated multidrug-resistant classical pathogen. Acinetobacter baumannii (A. baumannii) accounts for nearly 80% of reported Acinetobacter infections. A. baumannii resist desiccation, and survive for several months on animate and inanimate surfaces. It has excellent colonizing potential, and contact transmission is a big challenge intermittent as well as endemic outbreaks. Strong biofilm formation is a part of virulence pathogenesis strategies of this organisms, and elimination of the identified source often require multiple interventions. This review mainly discusses on relevant epidemiological features of A. baumannii.

IMPORTANCE

Once documented as a pathogen with low virulence, Acinetobacter is currently an important etiological agent of nosocomial infections, including hospital-acquired pneumonia and ventilator-associated pneumonia in patients admitted to intensive care units (ICUs), wound infections from war, and natural disasters such as a tsunami[1-3]. The National Nosocomial Infections Surveillance System reported a significant increase in the proportion of Acinetobacter among all Gram-negative aerobes during the 17 years of the study period (1986 through 2003)[2]. Acinetobacter was the only pathogen showing consistently increasing incidence in nosocomial pneumonias, and Acinetobacter baumannii (A. baumannii) was a major species among reported causes of nosocomial pneumonia[3].

Taxonomical aspect

The Gram-negative, non-fermentative aerobic bacteria which now recognized as belonging to the genus Acinetobacter have in the past been classified under various generic names. The genus Acinetobacter is now classified in the family Moraxillaceae, which includes Moraxella, Acinetobacter, Psychrobacter, and related organisms[4]. The genus Acinetobacter includes Gram-negative coccobacilli that have a G + C content of 39-47 mol% and that are strictly aerobic, non-motile, catalase-positive, and oxidase-negative. The negative oxidase test is important for rapid presumptive identification to differentiate the genus Acinetobacter from other similar non-fermentative organisms. But the transformation assay of Juni is the only test considered to be an unambiguous identification test for the genus Acinetobacter[5]. Most Acinetobacter species are non-fastidious and can be easily grown on simple microbiological media. Although variants appear, typical colonies are smooth, domed shaped pale yellow to grayish, about 2 mm with entire edge. Most species grow at ambient temperature, and pathogenic species such as A. baumannii grow well at 37 °C. Enrichment medium such as Leeds selective medium as occasionally use, and are helpful in recovery of isolates from complex samples[6].

The genus Acinetobacter encompasses at least 25 DNA groups (genospecies) identified by DNA-DNA hybridization, 23 of which have been officially validated[7-10]. A recently submitted species of Acinetobacter nosocomialis (A. nosocomialis) and A. pittii are included in taxonomic nomenclature. Acinetobacter uses a wide variety of organic compounds as a carbon sources. This property has been used in developing the identification system for this organism. It is often difficult in clinical laboratories to differentiate the isolates of Acinetobacter at the species level according to their phenotypic characteristics[8], and can be inadequate for species confirmation, and should be used with caution. Automated systems available for distinguishing Gram-negative pathogens can identify Acinetobacter species but have limitations. A. baumannii, Acinetobacter calcoaceticus (A. calcoaceticus), genomic species 3, and 13TU are closely related and formally grouped as A. baumannii-A. calcoaceticus (Abc) complex (recently species 3 and 13TU are referred as A. pittii and A. nosocomialis, respectively). Molecular characterization, particularly 16S rRNA gene sequence analysis, can be of great help to resolve matters of dispute. Looking at the global dissemination of international clones, and their involvement in outbreaks, the rapid and discriminating genotyping methods are required for delineation of such clonal lineages[11]. Among the most common methods that are currently used involves pulse-field gel electrophoresis, amplified fragment length polymorphism, single locus genotyping, trilocus sequence-based typing, multi-locus sequence typing such as PubMLST, Pasteur’s MLST, multi-locus variable-number tandem-repeats , resistance island typing, PCR with electrospray ionization mass spectrometry, next-generation whole genome sequencing, and PCR-based replicon of plasmid DNA. Most of these genotyping methods are not routinely used in hospitals and not cost effective, but extremely useful for to establish clonal relationships of the isolates and their taxonomical classification[11-15].

Habitat and colonization

Although Acinetobacter has emerged as an important pathogen, little is known about its natural reservoirs and habitat. Pathogenic members of the genus Acinetobacter contribute to the normal flora of human skin, upper respiratory tract, and gastrointestinal tract. The clinical consequences of Acinetobacter infections range from minimal to moderate to severe. A. baumannii, along with two other genetically closely related species (genomic species 3 and 13TU), is almost exclusively associated with human infection and is phenotypically difficult to differentiate routinely in clinical laboratories. Hence, the group is known as A. baumannii-A. calcoaceticus-complex (Abc-complex), and is often regarded A. baumannii in clinical practice as[16,17]. Although many consider A. baumannii to be ubiquitous, not everyone agrees. It is considered to be commensal with humans, and colonization is well documented. Therefore, the switch from colonization to infection is more favorable than it would be from more distant environmental sources[10]. Other species that are occasionally isolated from clinical samples are A. calcoaceticus, A. hemolyticus, Acinetobacter johnsonii (A. johnsonii), Acinetobacter lowffi, and Acinetobacter ursingii.

EPIDEMIOLOGICAL ASPECT

Acinetobacter species account for a substantial proportion of epidemic and endemic nosocomial infections and occasional sporadic outbreaks[14,16,18,19]. Geographically distant outbreaks are being studied for their ancestral genetic pool and clonal lineage. Multilocus sequence typing analysis recognized I to III international clones, corresponds to their clonal complexes, and many of the isolates causing outbreaks are suspected phylogenetically to be closely related with these clonal groups[20]. It can cause a wide array of infections such as respiratory tract infections, bloodstream infections, urinary tract infections, meningitis, endocarditis, and wound infections. In a recent report, 6 out of 7 patients with Acinetobacter bloodstream infections found A. baumannii colonizing their gastrointestinal tract[21]. A. baumannii is a prevalent species that causes epidemic outbreaks of nosocomial Acinetobacter infections[17,22-24]. Although there are mixed opinions, A. baumannii is usually reported to have a known natural habitat around patient population and in healthcare facilities and is occasionally isolated from environmental samples such as soil and water. A. baumannii is an excellent colonizer and is known to form biofilms. Furthermore, the reports demonstrate a positive correlation between biofilm formation capabilities and the multidrug resistance (MDR) status of A. baumannii. Such phenotypes have the ability to mediate outbreaks[25]. The multifactorial nature of the pathogenicity of A. baumannii has been documented recently and various models are proposed, and the involvement the presence and expression of exoproteases and exopolysaccharides (mediating biofilms), iron acquisition resistance to serum, resistance to desiccation, adherence and colonization, epithelial cell invasion and extraordinary ability to acquire foreign genetic material through lateral transfer for own survival, are elaborated as virulence attributes[26-31]. A. baumannii survives for a relatively long time in environments such as dry animate and inanimate surfaces and, when conditions are favorable, leads to outbreaks. The exact natural habitat of many of the Acinetobacter species is yet to be fully understood and may require intense efforts to identify.

Towner describes that depending on the site of isolation and the population of species or strains involved, Acinetobacter can be broadly categorized into three groups[10]: (1) MDR isolates capable of colonizing and infecting hospitalized patients, usually mediating hospital outbreaks. Generally these are A. baumannii. The isolates usually belong to a single clone or limited clones. Intensive care units are the depots for such outbreaks (occasionally other units mediate their spread as well); and (2) Relatively less resistant, less virulent strains that occasionally cause outbreaks. These isolates can be a part of normal skin flora of humans or animals or are associated with food spoilage[10,32]. Examples of such isolates are A. johnsonii, A. lwoffii, and A. radioresistens[33]. Environmental sources of isolate that are sensitive to many routine antibiotics and rarely cause outbreaks. A. calcoaceticus is a classic example. Infection control practices are therefore reserved mainly for the resistant isolates, which are usually A. baumannii-complex members. The patterns of spread of these members are also peculiar and can be correlated to strains causing outbreaks. In many European and Asian hospitals, the clonal spread (single clone) of A. baumannii has been reported either in a single hospital or in multiple hospitals and the strain was susceptible only to colistin and tigecycline[34,35]. Epidemiological typing methods are often helpful in delineating their dissemination and the strains involved in an outbreak and can differentiate epidemic outbreaks from sporadic strains. Thus, overall diversity of habitat, predilection to accumulate antimicrobial resistance, resistance to desiccation, ability to form biofilm, and propensity to cause hospital infection outbreaks make Acinetobacter an remarkable microorganism.

A. baumannii strains are generally more resistant than other species of this genus and often express a MDR phenotype, as discussed previously. Therefore, treatment of nosocomial infections caused by A. baumannii has become complicated because of the widespread antimicrobial resistance among these organisms[36]. The rising trend of resistance in A. baumannii strains, particularly to newer antimicrobial agents, is a health care concern. The organism expresses multiple mechanisms of antibiotic resistance that likely leads to the development of multiply resistant or even “pan-resistant” strains. This situation is particularly a quandary in terms of therapeutic choices for epidemic outbreaks mediated by these phenotypes.

POTENTIAL SOURCES OF INFECTION AND CONTAMINATION

The source of A. baumannii infections can be endogenous or exogenous. Most frequently, the infection is exogenous in origin because of the ability of the organisms to survive longer in the environment and on dry surfaces and because they are resistant to desiccation. A. baumannii multiply not only on human and animal skin, but also in soil and water and thus have a diversity of reservoirs. Locations in the hospital environment where A. baumannii have been found include ventilator tubing, suction catheters, humidifiers, containers of distilled water, urine collection jugs, intravenous nutrition, multidose vials of medication, potable water, moist bedding articles, pillows, and inadequately sterilized reusable arterial pressure transducers[37-39]. A. baumannii have been found in or on water taps, sinks, and computer keyboards and on all other inanimate surfaces that can act as a reservoir[40,41]. Hospital food can also be a potential source of Acinetobacter infection[8]. A study of two hospital outbreaks in Leiden, the Netherlands, reported the isolation of the outbreak strains from the dust inside the respiratory ventilator, the apparatus used to cool or warm a patient[40].

The gloves, gowns, and unwashed hands of hospital staff including doctors and nurses are frequently contaminated and may act as a potential source of Acinetobacter infection[14,42]. Hospital staffs with damaged skin are at increased risk of being colonized with Acinetobacter and are more likely to contaminate medical equipment and devices and patients by direct contact, thereby causing outbreaks of infection[43]. Specific types of medical procedures are also reportedly associated with high rates of infection with Acinetobacter, such as wound irrigation and treatment, catheterization, and tracheostomy[44]. Thus, the mode of infection can be environmental contamination or cross-contamination[45]. Community-acquired A. baumannii pneumonia is one of the severe forms of infection found around Indian Ocean, with very high co-morbidities and reportedly associated in part with casualties from natural disasters such as earthquake and tsunamis, and wound contamination occurring among soldiers following war-related injuries[46].

NOSOCOMIAL ACQUISITION AND RISK FACTORS

Several factors reported by different groups increase the risk of nosocomial infection with A. baumannii. Most vulnerable among them are mechanical ventilation (source of ventilator-associated pneumonia), intensive care and other critical care units, wound and burn units, prolonged hospital stay, prior antibiotic therapy, increased exposures to infected patients, colonized neighboring patients, and health care personnel. Other risk factors are a weakened immune system, chronic and debilitating disease, and diabetes. Infection secondary to an invasive procedure is widely reported and involves ventilator-associated pneumonia, secondary meningitis and bloodstream infection, urinary tract infection, surgical site infection, and catheter-related bloodstream infection. In most cases it is point source contamination. Postoperative complications from infection with A. baumannii have been reported; the major risk factors are skin and soft tissue, bone, central nervous system trauma or injuries, and combat wounds and injuries[47-49]. Post-disaster infections caused by A. baumannii have also been reported[50,51]. A. baumannii is intrinsically resistant to many antimicrobial agents and has a propensity to acquire resistance to other, newer antimicrobial agents as well[52]. Consequently, it has become more prevalent because of selective pressure from antimicrobial agents in ICUs. Analysis of the epidemiological profile of antibiotic-resistant Acinetobacter spp showed an increased risk of infection in patients in ICUs who probably spread large numbers of A. baumannii cells into their surroundings by shedding A. baumannii-infected or colonized cells, making the area more likely to be a source of infection for others[37,53]. Although airborne transmission has been documented, direct contact, including patient-to-patient and health care-provider-to-patient transmission, is more relevant.

Community acquisition of Acinetobacter infection, although rare, has been reported[54,55], and a community-acquired MDR Acinetobacter carrying IMP1 metallo-β-lactamase, responsible for hospital infection, is recovered[55]. Community-acquired A. baumannii pneumonia[56,57], community-acquired bacteremia[58], urinary tract infection[59], and meningitis[54] have been reported. On the basis of the rising incidence of community-acquired A. baumannii infection, a concurrent spread of multidrug resistance is the greatest risk. Among, A. baumannii wound infections, three hypotheses usually described are a combination of wound with environmental bacteria, a wound contamination from previous cutaneous or oropharyngeal endogenous reservoir, and hospital acquisition[46].

STRATEGIES TO CONTROL INFECTION

Outbreaks, particularly endemic or periodic epidemic outbreaks, caused by MDR A. baumannii are difficult to control. It is still possible to effectively control A. baumannii, although eradication is in question[14]. Decontamination of the patient by treating the gut and skin has been reported. Antibiotics can be used to inhibit gut colonization by A. baumannii that remains susceptible, but the benefits are limited because of the risk of developing resistant phenotypes. Additional research is needed to clarify the role of such techniques for selective decontamination of gut compared with surfaces such as skin[60]. The role of various sites of A. baumannii colonization and the risk of epidemiological outbreaks have been assessed; selective gut decontamination was found to be less effective as an additional measure[61]. Selective decontamination of skin with chlorhexidine reduced a significant load of A. baumannii and has been proposed as the infection control measure to lower the number of endemic outbreaks[62]. Because A. baumannii is widely present in the hospital environment, it can contaminate any surface or article with which it comes in contact, e.g., resuscitation bags, blood pressure cuffs, parenteral fluids and nutritional solutions, lotion dispensers, hand creams, bed linen, and mattresses. Therefore strict hand hygiene and personal cleanliness are essential in breaking the route of transmission[63]. Periodic disinfection of wards, units, and surfaces and sterilization of medical devices using appropriate methods are highly recommended. A periodic hospital environmental sample survey for microbiological contamination is advisable[64,65]. The epidemiological studies help to identify the source or reservoir of the infection and thus eventually to understand how to control the outbreaks[8]. Control of the environmental reservoir is a major part of an effective control strategy[64,66]. The researchers who conducted the study in the Netherlands controlled an outbreak by removing dust from the mechanical ventilator and continuous venovenous hemofiltration machines and replacing dust filters[40]. A study conducted in the United States reported A. baumannii as a model in eradication of MDR infections[67]. The control measures for A. baumannii infection have been discussed by many investigators[8,18,68,69]. Some of the specific control measures for A. baumannii infection are shown in Table 1.

Table 1 Some of the major infection control measures marked for Acinetobacter baumannii infection outbreaks.

Sr	Effective control measure	Ref
1	Early detection of a colonized patient or the source or reservoir of an infection	[14,70]
2	Eradication of the source or reservoir	[71]
3	Isolation of an infected or colonized patient into an isolation cubicle	[18]
4	Cohort nursing	[72]
5	Emphasis on hand washing (with alcoholic-based disinfectants) before and after patient handling	[73]
6	Use of disposable gloves and aprons	[42]
7	Prohibition of sale of antibiotics without prescription/judicious use of antibiotics	[69,74]
8	Improved surveillance system for antimicrobial resistance	[75]
9	Adherence to infection control best practices	[76]
10	Education of hospital staff and community for infection control/proper drug use and maintenance of hygiene/contact precaution	[77,78]

One of the most associated factors with reservoirs is biofilm formation capability of A. baumannii wherein it is responsible in part for the intermittent release of pathogens that leads to outbreaks. Biofilm formation by this organism also facilitates its persistence, and thus acts as a source of infection[25]. Recently, a dynamic exchange of gene cassettes between integrons (a mobile genetic element responsible for recruitment of multiple resistance genes, e.g., class 1 integron) in natural biofilms has been demonstrated[25,79]. This association of biofilm is important in higher tolerance or resistance to strong antimicrobial and biocidal agent[80]. Biofilm producing virulence is also found associated with aminoglycoside resistance genes. Rajamohan et al[25] demonstrated an increased biocide resistance and multidrug resistance in A. baumannii associated with the ability to form stronger biofilms. In part, the resistance may be increasing due to low penetration of antimicrobials into biofilms, in addition to acquisition of resistance genes through mobile genetic elements[81]. The continuous presence of high selection pressure of antimicrobials and disinfectants in intensive care units is also been correlated to increased multidrug resistance, strong biofilm abilities, and survival of these variant within such biofilms[16,82]. Thus control of such variants are a challenge, and difficult with routine antimicrobial and biocidal agents.

Microbiology laboratories can provide frontline surveillance for antibiotic resistance and are therefore useful in combating nosocomial infections[83]. Rapid, accurate analysis of antimicrobial susceptibility will be useful in determining the precise use of antimicrobial agents. Hence, clinical input from a microbiologist is necessary to keep one step ahead in controlling nosocomial infections. Periodic surveillance by molecular typing of isolates from patients is recommended for early detection of an epidemic strain, which consequently serves as an effective control measure[84]. Empiric antimicrobial therapy based on such observations is useful when laboratory findings are impeded for one reason or another[85,86]. Such therapy has been successful against pneumonias, ventilator-associated pneumonias, and bloodstream infections caused by A. baumannii, especially in critically ill patients[87-90], although some failures have also been reported, and caution is advised[91]. Empiric carbapenem therapy is a popular example of such a regime[14,92,93]. With the rise of carbapenem resistance in MDR phenotypes, this approach seemingly faces difficulties[14]. MDR is a common phenomenon associated with A. baumannii that is on the increase[10,94-96]. There are no clear guidelines to treat A. baumannii infections, and antipseudomonal broad-spectrum penicillins and cephalosporins and the members of other categories such as monobactams, aminoglycosides, fluoroquinolones, carbapenems, glycylcyclines, polymyxins, and β-lactamase inhibitors are used to control infections involving A. baumannii. Selection of the appropriate antimicrobial agent for empirical therapy is therefore challenging and has to be based on local institutional and hospital findings. Treatment decisions are usually made on a case-by-case basis by a health care provider. Empirical treatment therefore is likely to differ for a given geographic location[97]. Antibiotic susceptibility testing and other phenotypic tests for detecting double-disk synergy should be used as a guide, in addition to approved governing guidelines. Institutional data mining and retrospective analysis are often of great help in this regard and are advised by Towner[10].

Because of the limited choice of antimicrobial agents, A. baumannii infections are treated mainly with extended-spectrum β-lactams; β-lactams with β-lactamase inhibitors such as tazobactam or sulbactam; and carbapenems. Colistin and sulbactam are still relatively effective against infection caused by MDR A. baumannii, but an anticipatory fear of the development of resistance is increasing in ICUs. Peptides and other novel antibacterial agents are in the experimental phases. A combination therapy (dual or triple therapy) of a carbapenem with sulbactam, tobramycin, colistin, and aztreonam is being assessed in laboratory synergy studies, but clinical trials are required before one can adopt such combination regimens[98]. A study containing pharmacokinetic-pharmacodynamic profiling of four antimicrobial drugs against A. baumannii suggested that a combination involving carbapenem is required for effective therapy[99]. A glycopeptide (vancomycin or teicoplanin)-colistin combination was found to be highly active (synergism) against A. baumannii both in vitro and in a simple animal model[100]. A complicated case of persistent MDR A. baumannii central nervous system infection (ventriculitis) was resolved by a prolonged triple combination therapy involving intraventricular colistin and tobramycin plus intravenous colistin, rifampin, and vancomycin[101]. In murine pneumonia and rabbit meningitis models of A. baumannii infection, imipenem or sulbactam were found to be appropriate for combination therapy when used with rifampin[102]. A comparative in vitro study of synergistic activities also demonstrated that imipenem has better synergism with colistin than does amikacin or ampicillin/sulbactam against carbapenem-resistant A. baumannii[103]. In another study, tigecycline, a recently developed novel broad-spectrum antibacterial agent, was used (off-label indication) in combination therapy to treat MDR A. baumannii superinfection. However, the studies had several limitations such as retrospective design, small number of patients, and tigecycline as a part of the combination[56]. Despite its association with nephrotoxicity, colistin has been used by different modes of administration. Nebulized colistin was found to be more efficient in A. baumannii pulmonary infections when administered solely in nebulized form or in combination with intravenous colistin against intravenous colistin alone[104]. Colistin is still considered a good choice against MDR A. baumannii compared with ampicillin/sulbactam[105-107] or rifampin+imipenem[107]. The nephrotoxicity associated with colistin is reported to be reversible and less frequent than once thought. Neurotoxicity is rare, although more posological research is needed[33]. At present, no new drugs that could be available in 5 years are currently in the pipeline; therefore, combination regimens of antibiotics are the only resources to combat this infection.

ANTIMICROBIAL RESISTANCE IN A. BAUMANNII

The three major forces that drive antimicrobial drug resistance are failure to maintain hospital hygiene, selective pressure due to irrational use of antibiotics, and mobile genetic elements encoding the bacterial resistance mechanism[96]. The resistance among A. baumannii strains to β-lactam agents is of great concern among clinicians. The β-lactams are broadly accepted for treatment because of the availability of a wide range of drugs, their broad spectrum of activity, minimum side effects, and most importantly, their relatively low cost in developing countries of Africa, Asia and Latin America. The restriction on the use of these agents because of the emergence of resistance is a loss to the community and a great blow to the health care system. The mechanism of resistance to β-lactam in A. baumannii can be attributed to an intrinsic property or an acquired phenomenon. This organism is a known reservoir of multiple plasmids carrying antibiotic resistance markers[16,95]. The later mobile genetic element is of concern because the acquisition of resistance genes can radically change the scenario of drug resistance. Acinetobacter spp are also known to donate resistance-plasmids and are therefore likely to rapidly disseminate resistance among other commensals or pathogens.

Acinetobacter harbors multiple mechanisms of drug resistance. The mechanism of resistance to β-lactam agents in A. baumannii involves production of a variety of chromosomal or plasmid-mediated β-lactamases, especially extended-spectrum β-lactamase (ESBL), alteration of drug-binding proteins, permeability changes in the cell membrane, loss of porins, and efflux pump, of which the presence of an array of β-lactamases is the predominant weapon[108-111]. Acinetobacter produce a variety of β-lactamases. The main mechanisms of resistance to extended-spectrum cephalosporins in A. baumannii are the over-expression of chromosomal cephalosporinases and plasmid-encoded Ambler class A, B, and D β-lactamases[112]. ESBL-producing A. baumannii strains are now reported from various geographic areas of the world. These include the TEM type, SHV type, CTX-M type, PER-1, and VEB-1 β-lactamases. The prevalence of ESBLs is much higher in the isolates from ICUs than in isolates from other hospital sites[113,114]. A. baumannii produces a variety of extended-spectrum β-lactamases, depending on its geographical location. The PER-1 ESBLs were from Turkey, Korea, Russia, Romania, Belgium, France, and India; VEB-1, from France and Belgium; TEM-116 and TEM-92, from China and Italy, respectively; SHV-12 from the Netherlands; CTX-M-2 and CTX-M-43 from Korea and Bolivia (Italy), respectively[114-118]. Table 2 demonstrates in brief the representative mechanisms reported from different geographic locations. It was believed that ESBL-producing A. baumannii strains remain susceptible to carbapenems. However, OXA-type ESBL-producing A. baumannii isolates resistant to carbapenems have been widely reported, including from the United States[119-122] , that carry insertion sequence, ISAba1 upstream to OXA-like genes[123]. Although resistance in A. baumannii to polymyxins such as colistin is rare, recent reports suggest that an underlying mechanism of moderate resistance to colistin involves point mutation in pmrB, upregulation of pmrAB, and expression of pmrC, which lead to phosphoethanolamine modification of lipid A[33,124]. This finding means that we will not be able to use many more β-lactam drugs, which will further limit our options. Among carbapenem-resistant MDR A. baumannii, colistin is often the last resort. Recent findings suggest a slow rise of colistin-resistant isolates lead to Pan-drug resistant organisms[125]. With the help of rapid and powerful tools such as high throughput sequencing technologies e.g., whole-genome sequencing, one can elucidate the origin of large outbreaks of such resistant pathogens, and the exact genetics behind resistance mechanisms[125,126].

Table 2 Some of the commonly reported mechanisms of resistance in Acinetobacter baumannii from different geographic locations.

Category of mechanism	Gene involved	Geo-location	Ref
ESBL	PER-1 type	Hungary, India, Turkey, Korea, France, Belgium, Romania	[114,127-132]
ESBL	VEB-1 type	Belgium, France	[131,133]
ESBL	KPC type		[134]
ESBL	CTX-M-2 type	Japan	[135]
Carbapenemase	OXA type	United Kingdom, transcontinental	[120,136]
Carbapenemase	OXA type	United States,	[119,122,123,137]
Carbapenemase	OXA-51 type	United Kingdom, France, Iraq, United States	[123,138-140]
Carbapenemase	OXA-23 type	United Kingdom, China, United States	[141,142]
Carbapenemase	OXA-40 type	Spain, United States	[123,143]
Carbapenemase	OXA-58 type	Greece, Italy, Bolivia	[144,145]
Carbapenemase (multiple)	OXA, IMP, VIM	Korea	[146]
Carbapenemase, MBL	NDM	Israel, Germany	[147,148]
Carbapenemase, MBL	VIM	Poland	[149]
Carbapenemase, MBL	IMP	Japan, Brazil	[150,151]
Carbapenemase, MBL	SIM	China	[152]

ESBL: Extended-spectrum β-lactamase; MBL: Metallo-β-lactamase

FUTURE PROBLEMS

A contentment of multidrug resistance and their dissemination in Acinetobacter baummannii is not an easy task. While multiple drug resistance is increasing in this pathogen, and carbapenem resistance is rapidly spreading cross-continentally, there is a sharp decline in development of new antimicrobial agents that can control MDR A. baumannii. There is no new drug in pharmaceutical pipeline or none of the FDA-approved antimicrobial compounds tested had appreciable effect in control of MDR A. baumannii. The existing antimicrobials also failed to control the resistance development and effective elimination of MDR variants. A rational synergistic approach of some of the combination therapies although working, needs more in-depth understanding, and systematic studies are required in order to control probably outbreaks. Creation of pan-drug resistant variants will have to be avoided, and efforts on new anti-acinetobacter drug development would be invested.

CONCLUSION

Microbiological surveillance facilitates the ability to monitor changes in the trends of dominant microorganisms and their antimicrobial susceptibilities in hospitals. It helps to detect recent resistance mechanisms in these pathogens and to formulate antimicrobial usage policies for the hospital and adds to the epidemiological information about these organisms in particular regions of the country.

The MDR Acinetobacter clinical isolates, especially in the ICUs of hospitals, are a serious public health concern worldwide, and responsible for high mortality. The geographic variation in resistance patterns emphasizes the importance of local surveillance in determining the most suitable therapeutic option to treat Acinetobacter infections. The lack of therapeutic options for treating MDR organisms calls for systematic pharmacokinetic and pharmacodynamic studies of rational combination therapies until new, powerful drug appear in clinical practice for this purpose.

ACKNOWLEDGMENTS

Authors thank Pamela Fried of Drexel University College of Medicine Academic Publishing Services for editorial help with the manuscript.