Moganty R Rajeswari* and Jitendra Vashist

Department of Biochemistry, All India Institute of

Medical Sciences (AIIMS),

New Delhi - 110 029, India,

INTRODUCTION

Infections that occur during hospitalization but are not present or incubating upon hospital admission are defined as nosocomial (nosos = disease, komeo = to take care of). Nosocomial infections are one of the major health problems confronting clinicians in intensive care units.  Contribution of Acinetobacter baumannii to nosocomial infections has been increasing abruptly over the last 30 years and due to this reason, it is a problem of immediate concern. A. baumannii, a very common hospital pathogen in ICUs and wards has been identified as one of the six important and highly drug resistant hospital pathogens by the “Infectious Disease Society of America”(IDSA) (Boucher et al., 2009). Figure 1 shows the prevalence of A. baumannii among the nosocomial infectious bacteria.  

Fig. 1. PIE distribution of Nosocomial infection producing organisms.

Taxonomy features of Acinetobacter baumannii

In the taxonomy of bad bugs, Acinetobacter baumannii is classified as an opportunistic pathogen. A. baumannii belong to the lineage of Proteobacteria-Gammaproteobacteria- Pseudomonadales-Moraxellaceae. A. baumannii is a pleomorphic, metabolically versatile, ubiquitous, nonfermentative, catalase positive, oxidase negative, aerobic gram-negative pathogen, commonly isolated from the hospital environment and hospitalized patients.

A. baumannii do not have a fastidious growth requirement and are able to grow at various temperatures and pH conditions. These bacteria can grow in simple mineral medium containing ammonium or nitrate salts and a single carbon and energy source such as acetate, lactate or pyruvate. Their optimal temperature of growth is in the range of 35 - 45⁰C. The capacity to grow at 44⁰C serves as a distinguishing characteristic between A. baumannii and other genospecies.

Nosocomial Infections associated with A. baumannii

A. baumannii has recently emerged as an important nosocomial pathogen, mostly involving patients with impaired host defenses, especially in intensive care units, neonatal units and neurosurgical wards. They can cause infections in hospital patients, especially those who are already very ill, such as patients in intensive care units. It preys exclusively on the weakest of the weak and the sickest of the sick, slipping into the body through open wounds, catheters, and breathing tubes. A. baumannii has been isolated from various types of opportunistic infections, including septicemia, pneumonia, endocarditis, meningitis, skin and wound infection, and urinary tract infections (Kapil et al., 1998). Infections caused by A. baumannii usually involve organ systems with a high fluid content (e.g., respiratory tract, peritoneal fluid and urinary tract), manifesting as nosocomial pneumonia, infections associated with continuous ambulatory peritoneal dialysis (CAPD), or catheter-associated bacterimia. Studies on A. baumannii in various countries have shown a predominance of isolation from urine (21-27%) and tracheal-bronchial secretions (30-40%) (Villers et al.,1998). Reports on bloodstream infections from military medical hospitals for treating service members injured in Afghanistan and the Iraq/Kuwait region, together with similar reports during the Vietnam war, have raised the possibility of environmental contamination of wounds as a potential source (Davis et al., 2005).

In newborns, the elderly, burn victims, patients with depressed immune systems, and those on ventilators, A. baumannii infections can cause death. Death by A. baumannii can take many forms: catastrophic fever, pneumonia, meningitis, infections of the spine and sepsis of the blood. Patients who survive face longer hospital stays, more surgery, and severe complications. Patients with A. baumannii pneumonias occurring in the context of an outbreak in the intensive care unit (ICU) generally have a history of preceding contact with respiratory support monitors or equipment. It is believed by some clinicians that the recovery of A. baumannii in the hospitalized patient is an indicator of severe illness, with an associated mortality of approximately 30%.

Penetrance of A. baumannii in hospital settings

During the last two decades, hospital acquired infections involving multi-resistant A. baumannii isolates have been reported, often in association with contamination of the hospital equipment or cross-contamination by the colonized hands of patient attending personnel. It is often difficult to distinguish between infection and colonization with A. baumannii. Healthy people can carry the bacteria on their skin with no serious ill effects - a process known as colonization. Colonization poses no threat to people who are not already ill, but colonized health care workers and hospital visitors can carry the bacteria into neighboring wards and other medical facilities. Therefore, entrance of A. baumannii in hospital, through a colonized patient is the most likely mode. Adherence to host cells, as demonstrated in an in vitro model using bronchial epithelial cells is considered to be a first step in the colonization process. Figure 2 shows the factors that contribute to A. baumannii as environmental persistence and host infection and colonization. Once it enters a hospital ward, A. baumannii can spread from the colonized patient to the environment and other susceptible patients. The direct environment of the patient can become contaminated by excreta, air droplets and scales of skin. A. baumannii is often cultured from hospitalized patients sputum or respiratory secretions, wounds, and urine. 

A. baumannii also colonizes irrigating solutions and intravenous solutions. A. baumannii does not have fastidious growth requirements and is able to grow at various temperatures and pH conditions. Hence, the contaminated environment can become a reservoir from which the organism can spread. The versatile organism exploits a variety of both carbon and energy sources. These properties explain the ability of Acinetobacter species to persist in either moist or dry conditions in the hospital environment, thereby contributing to transmission. This hardiness, combined with its intrinsic resistance to many antimicrobial agents, contributes to the organism’s fitness and enables it to spread in the hospital setting.

Fig. 2. The factors that contribute to Acinetobacter baumannii environmental persistence and host infection and colonization

Pathogenic factors associated with A. baumannii infections

Outgrowth on mucosal surfaces and medical devices, such as intravascular catheters and endotracheal tubes can result in biofilm formation, which enhances the risk of infection of the bloodstream and airways. Experimental studies have identified various factors that could have a role in A. baumannii infection, for example, lipopolysaccharide has been shown to elicit a proinflammatory response in animal models (Knapp et al., 2006). Furthermore, the A. baumannii outer membrane protein A has been demonstrated to cause cell death in vitro (Choi et al., 2008). Iron-acquisition mechanisms and resistance to the bactericidal activity of human serum are considered to be important for survival in the blood during bloodstream infections. Environmental survival and growth require attributes such as resistance to desiccation, versatility in growth requirements, biofilm forming capacity and probably, quorum-sensing activity (Smith et al., 2007). Finally, adequate stress response mechanisms are thought to be required for adaptation to different conditions.

Global Scenario of resistance patterns of A. baumannii

Among all the bacterial pathogens, which are associated with the infections in hospitals, A. baumannii has a large contribution in all around the world. A. baumannii was also considered as the main culprit for the death of soldiers during Iraq war and globally, most of the clinical attentions were insight after the disaster of war (Davis et al., 2005). Many reports have come regarding the outbreaks and pathology of A. baumannii (Boucher et al., 2009). About twelve hundred references are cited since 1987 and approximately one quarter of the PubMed citations for “nosocomial Acinetobacter” appeared in 2005 and 2009. An increasing number of reports globally suggest that A. baumannii have become important nosocomial pathogens, which account for about 8-10% of gram negative bacterial infections.

Effective treatments for A. baumannii infections

Few antibiotics are effective for the treatment of A. baumannii infections because of the resistance accumulated by isolates and the frequency of multidrug-resistant strains (Davis et al., 2005). The group of antibiotics, which usually are used by clinicians all around the world are β-lactams, aminoglycosides and quinolones. Currently many nosocomial isolates are resistant to all these major classes of antibiotics and therefore, these strains are referred to as Multi Drug Resistant (MDR) organisms. The most challenging part of these strains is the extensive antimicrobial drug resistance. Today, resistance has rendered most of the original antibiotics obsolete for many infections, mandating an increased reliance on synthetic drugs. Almost 25 years ago, researchers observed acquired resistance of A. baumannii to antimicrobial drugs commonly used at that time, among them being aminopenicillins, ureidopenicillins, first and second generation cephalosporins, cephamycins, most aminoglycosides, chloramphenicol, and tetracycline.

As A. baumannii infections are often difficult to treat, a combination therapy is usually done for effective treatment. The combination of antibiotics include ampicilin-sulbactam, combinations of imipenem and clavanate, imipenem + tobramicin, polymyxin B +sulbactam etc. Clinical data are too few to recommend the use of specific combination regimens for the treatment of infections caused by MDR strains of A. baumannii, but combination therapy might be considered by clinicians in order to achieve synergistic activity and to maximize antimicrobial effectiveness (as well as to minimize the possibility of emergence of further resistance) in severely ill patients for whom therapeutic options are otherwise limited.

Resistance  mechanisms

One of the biggest issues with treating A. baumannii is that the bacterium is naturally resistant to a number of antibiotics, making it challenging to find a drug regime which will effectively attack it in an infected patient. Generally, A. baumannii exploits all the stratagems via multigenic phenomenon to escape from mortal effects of antibiotics.  Documented mechanisms of resistance in A. baumannii are aminoglycosides-modifying enzymes, broad-spectrum β-lactamases, altered penicillin-binding proteins, quantitative and/or qualitative changes in outer membrane porins (Vashist and Rajeswari, 2006). Differential expression of membrane proteins in susceptible and highly resistant strains of A. baumannii from different parts of the world clearly show a strong association with the emergence of the resistance phenotype (Vashist  et al., 2010). All the above features of A. baumannii make this organism special for urgent medical investigations. More effective preventive measures are needed to cure the A. baumannii infections and to combat the spread of these MDR organisms.

References

Boucher, H.W., Talbot, G.H., Bradley, J.S., Edwards, J.E., Gilbert, D. and Rice, L.B. (2009)  Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin. Infect. Dis. 48, 1 - 12.

Choi C. H., Hyun S. H., Lee J. Y., Lee J. S., Lee Y. S., Kim S. A., Chae J. P., Yoo S. M. and Lee J. C. (2008) Acinetobacter baumannii outer membrane protein A targets the nucleus and induces cytotoxicity. Cell Microbiol. 30, 309 - 319.

Davis, K. A., Moran, K. A., Mcallister, C. K. and  Gray, P. J. (2005) Multidrug- resistant Acinetobacter extremity infections in soldiers. Emerg. Infect. Dis. 11, 1218 - 1224.

Kapil, A., Gulati, S., Goel, V., kumar, L., Rakhee, U. and Kochupillai, V. (1998) Outbreak of nosocomial Acinetobacter baumannii bacteremia in a high risk ward. Medical oncology. 15, 270 - 274.

Knapp, S. Wieland, C.W., Florquin, S., Pantophlet, R., Dijkshoorn, L. and Tshimbalanga, N. (2006) Differential roles of CD14 and toll-like receptors 4 and 2 in murine Acinetobacter pneumonia. Am. J. Respir. Crit. Care Med. 173, 122 - 129.

Smith, M.G., Gianoulis, T.A., Pukatzki, S., Mekalanos, J. J., Ornston, L. N., Gerstein, M. and Snyder, M. (2007) New insights into Acinetobacter baumannii pathogenesis revealed by high-density pyrosequencing and transposon mutagenesis. Genes Dev. 21, 601 - 614.

Vashist, J. and Rajeswari, M.R. (2006) Structural investigations of novel porin OmpAb of Acinetobacter baumannii. J. Biomol. Struct. Dyn. 24, 243 - 253.

Vashist, J., Tiwari, V., Kapil, A., Rajeswari, MR., (2010) Quantitative profiling and identification of outer membrane proteins of beta-lactam resistant strain of Acinetobacter baumannii. J. Proteome Res. 5, 1121 - 8.

Villers, D., Espaze, E., Coste-Burel (1998) Nosocomial Acinetobacter baumannii infections: microbiological and clinical epidemiology. Ann. Intern. Med.129, 182 - 9.