Acinetobacter baumannii: A Brief Account of Mechanisms of Multidrug Resistance and Current and Future Therapeutic Management

Acinetobacter baumannii, a non-motile, glucose non fermentative, oxidase negative, encapsulated, gram-negative coccobacillus, has recently gained importance because of its increasing resistance to the available antibiotics. Three main mechanisms of resistance in A. baumannii are: enzymes inactivating antibiotics, reduced entry into the target site of bacteria and alteration of the target or cellular functions due to mutations. Multi-drug resistant A. Baumannii, including carbapenam resistant A. Baumannii, are posing a potential threat to mankind by causing lethal infections, especially in ICU set up and in patients who are on ventilators, for which our conventional antibiotics were not shown to be effective. Many reports have indicated carbapenam resistance among A. Baumannii and only colistin and tigecyclyne have shown some promise in combating this lethal microorganism.

The genus, Acinetobacter, as has been currently defined, comprises gram-negative, strictly aerobic, non-fermenting, non-fastidious, non-motile, catalase-positive, oxidase-negative bacteria. This genus has undergone significant taxonomic modifications over the last 30 years. Its most important representative, Acinetobacter baumannii, has recently emerged as one of the most troublesome pathogens in health care setups. Its clinical significance, especially over the past 15 years, has been propelled by its remarkable ability in upregulating or acquiring resistance determinants, thus making it one of the organisms which threaten the current antibiotic era [1].

Acinetobacter baumannii (A. baumannii) is an encapsulated gram-negative coccobacilli containing proteins, namely porins and efflux channels, on the outer cell membrane, which mainly contribute to their resistance mechanisms [2]. However, as compared to other gram negative bacteria, it has fewer and smaller porin channels, which thereby decrease its cell permeability and increase its antibiotic resistance [3]. It was also discovered that the cell wall of the bacteria changes according to the environmental conditions, thus causing an increase in its thickness when it is placed in a very dry conditions, thereby again providing extra resistance at high temperatures also [4].

A. baumannii is generally considered to cause opportunistic infections and it is found to be non-pathogenic in healthy individuals [5]. Most of the cases are usually seen in the intensive care units (ICUs) of hospitals, in patients with deprived immunity and in those who are on various invasive equipments, like ventilator machines and catheters (causing various infections such as pneumonia, meningitis, septicaemia, and urinary tract infections). The irrational use of antibiotics in the ICU set up and the various bacterial mechanisms of resistance contribute to summation of resistance function for this untreatable, risky microorganism [6]. Risk factors [4–6] for colonization or infection with multidrug-resistant A. baumannii are:

There is rising concern about antimicrobial resistance among Acinetobacter species since the past decade [7]. Presence of the porin channels, efflux mechanisms and the non static behaviour of the bacteria in hot and humid conditions equip the species with extensive antimicrobial resistance [8].

The three main mechanisms of resistance are [9].

A. baumannii Is labelled as MDR-Ab when it is resistant to more than two of the following five classes of antibiotics [1,14].

In the past years, carbapenems were considered as the most important agents for the treatment of infections caused by MDR-A. baumannii. Carbapenem resistant A. baumannii (CRAB) is now emerging as a potential threat [15,16] and it is usually resistant to almost all antimicrobial classes except colistin and tigecycline, which have shown some promise against this organism [15,16].

The most important mechanism of carbapenem resistance in A. baumannii is enzyme inactivation by the production of beta-lactamases, which hydrolyze the carbapenams. These hydrolyzing enzymes include metallo-β-lactamases (which have been sporadically reported in some parts) and class D β-lactamases (widespread). The main gene clusters responsible for this resistance are blaOXA-23-, blaOXA-24/40-, and blaOXA-58-like gene clusters. They are identified either in the chromosome or in plasmids of A. Baumannii strains [15]. Another mechanism of reduced susceptibility to carbapenems are:

These factors may together lead to a high-level carbapenam resistance in these bacteria.

Sulbactam: Beta-lactamase inhibitors possess the greatest intrinsic bactericidal activity against A. baumannii isolates. This was evident from the study of Urban et al., [17], in which a clinical efficacy wise improvement was observed in 9 out of 10 seriously ill patients who were on mechanical ventilation, with the combinational ampicillin-sulbactam being given at a dosage of 3 g of amicillin and 1.5 g of sulbactam IV, three times a day. The clinical improvement was also comparable with other system involvements like pneumonia and blood stream infections [18]. In blood stream infections caused by this strain, treatment with a combination of sulbactam and ampicillin was found to be statistically significant in reducing the mortality, which was seen in a study conducted in Israel in situations of multi-drug resistance [19]. In meningitis, the combination was not found to be so beneficial. The dosage recommended is around 6g/day in divided doses with normal renal parameters.

Carbapenems: Carbapenems were found to have an excellent intrinsic bactericidal activity and they remain the most effective treatment against beta-lactamases and infections caused by multidrug-resistant A. baumannii. In some studies [20, 21], variations in the resistance patterns against imepenem and meropenem were seen . Discordant results have been obtained between the various carbapenems against a few isolates of A. baumannii [22] However, increasing numbers of CRAB isolates have been reported, which dramatically reduce the existing therapeutic options and pose a potential threat to public health. This resistant type A. baumannii is known to cause serious central nervous system (CNS) infections i.e. meningitis and ventriculitis, especially in patients undergoing neurosurgical procedures or head trauma. Significant mortality rates (20%-27% have been reported in different case series [23].

Aminoglycosides: Among aminoglycosides, amikacin and tobramycin are agents that retain activity against many A. baumannii isolates. There is a concern regarding its toxicity profile and as with other drugs, their resistance were growing with increased toxicity. A study [24] which compared the activity and toxicity of tobramycin against colistin demonstrated no statistical significance between these two in mortality also. In a study done by Hallal A et al., [25], the efficacy and safety of inhaled and intravenous tobramycin were compared, in which inhaled tobramycin proved to be little better than the intravenous one.

Polymyxins: in the past, the use of colistin was limited because of toxicity concerns and increasing availability of newer and safer antibiotics. However, in recent times, with increasing incidence of MDR-Ab, lack of effective antibiotics and reasonable activity of colistin against MDR-Ab have made it a useful drug against this organism [26].

Colistin and polymyxin B are the polymyxins used for the multidrug resistant A.baumannii. Colistin is most commonly used drug among the two. The toxicity (mainly, the nephrotoxicity) is the main concern in this group. It has been used for carbapenem-resistant cases, either IV polymyxin plus an intrathecal or intraventricularpolymyxin or aminoglycoside, with or without IV rifampin [27]. The dosing recommended by the Infectious Diseases Society of America for adults is 10 mg daily of colistin or 5 mg daily of polymyxin B [28].

Tigecycline: Tigecycline is a new glycylcycline agent which has shown bacteriostatic activity against MDR- Acinetobacter species [29]. A high level of resistance has now been documented by this drug, which has shown overexpression of efflux pumps in the strain. [30] In recent studies, Acinetobacter isolates with a decreased susceptibility to tigecycline, due to overexpression of a multidrug efflux pumps, was documented [31,32], but still, tigecycline is an effective alternative for salvage therapy when it is properly administered by experts.

Combination therapy: In the setting of an increased number of A. baumannii infections, treatment of those caused by carbapenem-resistant strains, susceptible only to colistin, has become a major problem during the past years. So, an appropriate combination therapy is of great importance, for tackling these infections

In a study, combination therapy with a carbapenem and a sulbactam led to favourable clinical outcomes in four critically ill patients who presented with MDR- Ab bacteraemia. The authors also conducted an in vitro study which showed that this combination was synergistic and that it showed an enhanced antibacterial activity against MDR- A. baumannii. Thus, a carbapenem-sulbactam combination can serve as an alternative in setups where colistin and tigecycline are not available for clinical use [33].

The combination of polymixins and intra-ventricular aminoglycosides has been considered as a good option for treating meningitis caused by CRAB species. But due to lack of newer agents and increasing resistance to the available antibiotics, it will be very difficult to treat meningitis caused by Acinetobacter in the future [27].

In another study, the combination of a rifampicin/imipenem was tried for the treatment of CRAB infections, but disappointing results were obtained [34].

In a study, the authors compared monotherapy and combination therapy with ampicillin/sulbactam, doripenem and tigecycline against MDR-Ab using an in vitro pharmacodynamic model. Although specific combination regimens displayed an additive activity at aggressive doses against these MDR-Ab, none of the regimens was able to maintain reductions in colony forming units against the more resistant isolates [35].

Recent data has suggested that glycopeptides, in particular, vancomycin, may have a unique activity against laboratory-adapted and clinical strains of A. baumannii, alone and in combination with colistin. In an in vivo study, the authors studied the effect of combinations of vancomycin, colistin, and doripenem on clinical strains of CRAB and found promising results. Their findings suggested that regimens containing vancomycin may confer a therapeutic benefit against infections caused by CRAB [36].

New β-lactamase inhibitors [1,37].

Compounds targeting the β-lactamases, especially the Ambler class B MBLs, can play an important role in halting the emergence of carbapenem resistance in A. baumannii. Their structures and catalytic mechanisms of these enzymes are zinc dependent and hence, they are more difficult to tackle with current β-lactamase inhibitors. Newer agents that are able to chelate the active Zn²⁺ site can turn out to be a promising therapy against this notorious organism. But several challenges are present, which make it difficult e.g presence of significant differences in the active site architecture between MBL types, the ability to develop a pan-MBL inhibitor. Also, MBLs have homologous mammalian enzymes and therefore, they can increase the risk for significant toxicity. Despite these problems, the development of compounds that target these enzymes continues.

The inhibitors of both aminoglycoside-inactivating enzymes and multidrug efflux pumps have also been troubled by diverse targets, with bacteria often harbouring multiple enzyme or pump types. More recently, cationic antimicrobial peptides that are capable of inhibiting both aminoglycoside phosphotransferases and acetyl transferases have been described. The importance of multidrug efflux pumps in A. baumannii is increasingly being recognized, with tigecycline being recently identified as a substrate of the RND-type pump Ade ABC. Through a large-scale in vitro screening, a range of efflux pump inhibitors has been identified (plant alkaloids and some synthetic compounds). Unfortunately, progress has been slow, with agents such as phenyl-arginine-β-naphthylamide showing a very good in vitro response, but being disappointing due to their toxicity concerns. Another major concern is that a variety of efflux systems are available in gram-negative organisms, which lead to a compensatory upregulation of noninhibited pumps.

These cationic peptides are ubiquitous elements of the innate immune response in a variety of invertebrate, plant, and animal species. They primarily act by disturbing the cell membranes and they have a structure and charge profile similar to those of the polymyxins, but the final steps in pathogen lethality are different. This mechanistic difference is clinically attractive and it has been well illustrated by the susceptibility of polymyxin-resistant A. baumannii strains to such peptides. Bactericidal activity against A. baumannii has been reported, on using both in vitro and in vivo models. Combination studies, as determined by fractional inhibitory indexes, demonstrated that magainin II (an antimicrobial peptide) acts synergistically with β-lactams against MDR- Ab.

From above discussion, it is clear that multidrug-resistant Acinetobacter infections are associated with extremely high crude mortality rates and most commonly, in severely ill patients. These infections are associated with increased times on mechanical ventilation, in ICUs, and in hospitals. Treatment options are limited; carbapenems and colistin are the current agents of choice for the most drug-resistant infections. The roles of other agents and combination therapy remains unclear. The development of new medications, properly conducted clinical trials of existing regimens and their combinations, more research and preventive measures for reducing the transmission of multidrug-resistant Acinetobacter infection, are urgently needed.

[1]. Peleg AY, Seifert H, Paterson DL, Acinetobacter baumannii: emergence of a successful pathogen Clin Microbiol Rev 2008 1(3):538-582.  [Google Scholar]

[2]. van Looveren M, Goossens H, ARPAC Steering Group. “Antimicrobial resistance of Acinetobacter spp. in Europe.” Clinical Microbiology and Infection 2004 10(8):684-704.  [Google Scholar]

[3]. Vila J, Marti S, Sanchez-Cespedes J, “Porins, efflux pumps and multidrug resistance in Acinetobacter baumannii.” Journal of Antimicrobial Chemotherapy 2007 59(6):1210-5.  [Google Scholar]

[4]. Houang ET, Sormunen RT, Lai L, Chan CY, Leong AS, “Effect of desiccation on the ultrastructural appearances of Acinetobacter baumannii and Acinetobacter lwoffii J. Clin. Pathol 1998 51(10):786-8.  [Google Scholar]

[5]. Fournier PE, Vallenet D, Barbe V, Audic S, Ogata H, Poirel L, “Comparative genomics of multidrug resistance in Acinetobacter baumannii” PLOS Genet 2006 2:e7  [Google Scholar]

[6]. Hujer KM, Hujer AM, Hulten EA, Bajaksouzian S, Adams JM, Donskey CS, Analysis of antibiotic resistance genes in multidrug-resistant Acinetobacter sp. isolates from military and civilian patients treated at the Walter Reed Army Medical Center Antimicrobial Agents and Chemotherapy 2006 50(12):4114-123.  [Google Scholar]

[7]. Lockhart SR, Abramson MA, Beekmann SE, Gallagher G, Riedel S, Diekema DJ, Antimicrobial resistance among gram negative bacilli as causes of infections in intensive care unit patients in the United States between 1993 and 2004 J Clin Microbiol 2007 45:3352-359.  [Google Scholar]

[8]. Bonomo RA, Szabo D, Mechanisms of multidrug resistance in Acinetobacter species and Pseudomonas aeruginosa Clin Infect Dis 2006 43(Suppl 2):49-56.  [Google Scholar]

[9]. Rice LB, Challenges in identifying new antimicrobial agents effective for treating infections with Acinetobacter baumannii and Pseudomonas aeruginosa Clin Infect Dis 2006 43(Suppl 2):100-05.  [Google Scholar]

[10]. Brown S, Amyes S, OXA b-lactamases in Acinetobacter: the story so far J Antimicrob Chemother 2006 57:1-3.  [Google Scholar]

[11]. Thomson JM, Bonomo RA, The threat of antibiotic resistance in gram-negative pathogenic bacteria: beta-lactams in peril! Curr Opin Microbiol 2005 8:518-24.  [Google Scholar]

[12]. Mussi MA, Limansky AS, Viale AM, Acquisition of resistance to carbapenems in multidrug-resistant clinical strains of Acinetobacter baumannii: natural insertional inactivation of a gene encoding a member of a novel family of beta-barrel outer membrane proteins Antimicrob Agents Chemother 2005 49:1432-440.  [Google Scholar]

[13]. Li J, Nation RL, Milne RW, Turnidge JD, Coulthard K, Evaluation of colistin as an agent against multi-resistant gram-negative bacteria Int J Antimicrob Agents 2005 25:11-25.  [Google Scholar]

[14]. Guide to the Elimination of Multidrug-resistant Acinetobacter baumannii Transmission in Healthcare Settings. An APIC Guide. 2010. Available from http://www.apic.org/rei//b8b0b11f-1808-4615-890b-f652d116ba56/file/apic-ab-guide.pdf. Accessed on 2013 Apr 19  [Google Scholar]

[15]. Poirel L, Nordmann P, Carbapenem resistance in Acinetobacter baumannii: mechanisms and epidemiology Clin Microbiol Infect 2006 12:826-36.  [Google Scholar]

[16]. Zarrilli R, Giannouli M, Tomasone F, Triassi M, Tsakris A, Carbapenem resistance in Acinetobacter baumannii: the molecular epidemic features of an emerging problem in health care facilities J Infect Dev Ctries 2009 3(5):335-41.  [Google Scholar]

[17]. Urban C, Go E, Mariano N, Berger BJ, Avraham I, Rubin D, Effect of sulbactam on infections caused by imipenem-resistant Acinetobacter calcoaceticus biotype anitratus J Infect Dis 1993 167(2):448-51.  [Google Scholar]

[18]. Jellison TK, Mckinnon PS, Rybak MJ, Epidemiology, resistance, and outcomes of Acinetobacter baumannii bacteremia treated with imipenem-cilastatin or ampicillin-sulbactam Pharmacotherapy 2001 21(2):142-48.  [Google Scholar]

[19]. Smolyakov R, Borer A, Riesenberg K, Schlaeffer F, Alkan M, Porath A, Nosocomial multi-drug resistant Acinetobacter baumannii bloodstream infection: risk factors and outcome with ampicillin-sulbactam treatment J Hosp Infect 2003 54(1):32-38.  [Google Scholar]

[20]. Norskov-Lauritsen N, Marchandin H, Dowzicky MJ, Antimicrobial susceptibility of tigecycline and comparators against bacterial isolates collected as part of the TEST study in Europe (2004–2007) Int J Antimicrob Agents 2009 34(2):121-30.  [Google Scholar]

[21]. Ikonomidis A, Pournaras S, Maniatis AN, Legakis NJ, Tsakris A, Discordance of meropenem versus imipenem activity against Acinetobacter baumannii Int J Antimicrob Agents 2006 28(4):376-77.  [Google Scholar]

[22]. Paterson DL, Depestel DD, Doripenem Clin Infect Dis 2009 49(2):291-98.  [Google Scholar]

[23]. Katragkou A, Roilides E, Infections with Colistin baumannii Central Nervous System Multidrug-Resistant Acinetobacter J. Clin. Microbiol 2005 43(9):4916-917.  [Google Scholar]

[24]. Gounden R, Bamford C, van Zyl-Smit R, Cohen K, Maartens G, Safety and effectiveness of colistin compared with tobramycin for multi-drug resistant Acinetobacter baumannii infections BMC Infect Dis 2009 9:26  [Google Scholar]

[25]. Hallal A, Cohn SM, Namias N, Habib F, Baracco G, Manning RJ, Aerosolized tobramycin in the treatment of ventilator-associated pneumonia: a pilot study Surg Infect Larchmt 2007 8(1):73-82.  [Google Scholar]

[26]. Jain R, Danziger LH, Multidrug-resistant Acinetobacter infections: an emerging challenge to clinicians Ann. Pharmacother 2004 38:1449-459.  [Google Scholar]

[27]. Kim BN, Peleg AY, Lodise TP, Lipman J, Li J, Nation R, Management of meningitis due to antibiotic-resistant Acinetobacter species Lancet Infect Dis 2009 9(4):245-55.  [Google Scholar]

[28]. Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, Practice guidelines for the management of bacterial meningitis Clin Infect Dis 2004 39(9):1267-284.  [Google Scholar]

[29]. Pachon-Ibanez ME, Jimenez-Mejias ME, Pichardo C, Llanos AC, Pachon J, Activity of tigecycline (GAR-936) against Acinetobacter baumannii strains, including those resistant to imipenem Antimicrob Agents Chemother 2004 48:4479-481.  [Google Scholar]

[30]. Ruzin A, Keeney D, Bradford PA, Ade ABC multidrug efflux pump is associated with decreased susceptibility to tigecycline in Acinetobacter calcoaceticus-Acinetobacter baumannii complex J Antimicrob Chemother 2007 59:1001-004.  [Google Scholar]

[31]. Maragakis LL, Perl TM, Acinetobacter baumannii: Epidemiology, Anti-microbial Resistance, and Treatment Options Clinical Infectious Diseases 2008 46:1254-263.  [Google Scholar]

[32]. Peleg AY, Adams J, Paterson DL, Tigecycline efflux as a mechanism for nonsusceptibility in Acinetobacter baumannii Antimicrob Agents Chemother 2007 51:2065-069.  [Google Scholar]

[33]. Lee NY, Wang CL, Chuang YC, Yu WL, Lee HC, Chang CM, Combination carbapenem-sulbactam therapy for critically ill patients with multidrug-resistant Acinetobacter baumannii bacteremia: four case reports and an in vitro combination synergy study Pharmacotherapy 2007 Nov 27(11):1506-511.  [Google Scholar]

[34]. Saballs M, Pujol M, Tubau F, Peña C, Montero A, Domínguez MA, Rifampicin/imipenem combination in the treatment of carbapenem-resistant Acinetobacterbaumannii infections J Antimicrob Chemother 2006 58(3):697-700.  [Google Scholar]

[35]. Housman ST, Hagihara M, Nicolau DP, Kuti JL, In vitro pharmacodynamics of human simulated exposures of ampicillin/sulbactam, doripenemand tigecycline alone and in combination against multidrug-resistant Acinetobacter baumannii J of Antimicrob Chemother 2013 [Epub ahead of print]  [Google Scholar]

[36]. O’Hara JA, Ambe LA, Casella LG, Townsend BM, Pelletier MR, Ernst RK, Activities of vancomycin-containing regimens against colistin-resistant Acinetobacter baumannii clinical strains Antimicrob Agents Chemother 2013 57(5):2103-108.  [Google Scholar]

[37]. Toney JH, Metallo-beta-lactamase inhibitors: could they give old antibacterials new life? Curr. Opin. Investig. Drugs 2003 4:115-16.  [Google Scholar]

[38]. Boehr DD, Draker KA, Koteva K, Bains M, Hancock RE, Wright GD, Broad-spectrum peptide inhibitors of aminoglycoside antibiotic resistance enzymes Chem Biol 2003 10(2):189-96.  [Google Scholar]

[39]. Piddock LJ, Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria Clin Microbiol Rev 2006 19(2):382-402.  [Google Scholar]

[40]. Brogden KA, Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 2005 3(3):238-50.  [Google Scholar]

[41]. Giacometti AO, Cirioni MS, Del Prete F, Barchiesi AM, Paggi E, Petrelli Comparative activities of polycationic peptides and clinically used antimicrobial agents against multidrug-resistant nosocomial isolates of Acinetobacter baumannii J Antimicrob Chemother 2000 46:807-10.  [Google Scholar]

[42]. Cai Y, Chai D, Wang R, Liang B, Bai N, Colistin resistance of Acinetobacter baumannii: clinical reports, mechanisms and antimicrobial strategies J Antimicrob Chemother 2012 67(7):1607-615.  [Google Scholar]