ReviewEmergence of resistance to carbapenems in Acinetobacter baumannii in Europe: clinical impact and therapeutic options
Introduction
Acinetobacter baumannii is a Gram-negative coccobacillus that has emerged over the last decade as a cause of healthcare-associated infections and sometimes of community-acquired infections [1]. Although in the 1960s it was considered to be of relatively low-grade pathogenicity and was ignored when isolated from clinical samples [2], A. baumannii has become one of the most important pathogens, particularly in the Intensive Care Unit (ICU) [3].
Nosocomial A. baumannii infections in critically ill patients include ventilator-associated pneumonia (VAP), bloodstream infection (BSI), wound infections and nosocomial meningitis, whereas community-acquired infections include mainly pneumonia and wound infections in unusual situations, such as in victims of an earthquake or war-related wounds in Iraq and Afghanistan [4], [5].
Factors predisposing patients to A. baumannii infections include previous antibiotic therapy, major surgery, burns, immunosuppression and the presence of invasive devices, especially mechanical ventilation [3], [6]. One of the main reasons for the current increased interest in A. baumannii is its remarkable ability to acquire and accumulate resistance determinants leading to the emergence of multidrug-resistant (MDR) strains and outbreaks [7]. This bacterium is also able to survive for prolonged periods throughout the hospital environment, potentiating its ability for nosocomial outbreaks. In the ICU, up to 30% of A. baumannii clinical isolates are resistant to at least three classes of antibiotics, often including fluoroquinolones and carbapenems [7].
Until recently, most A. baumannii isolates remained susceptible to carbapenems, although resistance to these compounds had been reported since the early 1990s [8]. Carbapenem resistance in this species is now increasingly observed worldwide and constitutes a sentinel event for emerging antimicrobial resistance [9]. Carbapenem-resistant A. baumannii is now considered a significant health problem because of the limited options for antibiotic treatment. In these MDR strains, colistin (also known as polymyxin E) is often the treatment of last resort, but colistin-resistant clinical isolates have already been reported [10], [11], [12], [13], [14].
A literature search from 1980 to 1999 found only 139 citations for A. baumannii compared with more than 2000 citations from 1999 to the end of 2010. Fig. 1 represents the number of citations found in PubMed from 1999 to the end of 2010 using either ‘Acinetobacter baumannii’ or ‘Acinetobacter baumannii and antibiotic resistance’, demonstrating the increasing burden of and interest in this bacterium at the beginning of the 21st century. Interestingly, the rise in citations was clearly correlated with the problem of antibiotic resistance, which represents 65% of all citations for A. baumannii from 2005 to 2010 (Fig. 1). Finally, citations for A. baumannii and outbreaks represent 18.2% (239/1312) of all citations from 1999 to 2010. Current knowledge about A. baumannii, including biological and epidemiological aspects as well as resistance to antibiotics and antibiotic therapy, are reviewed in this article, in addition to therapeutic recommendations.
Section snippets
Genome sequencing reveals a high plasticity of the Acinetobacter baumannii genome and the presence of hot-spots for acquisition of ‘resistance islands’ (Fig. 2)
In 2006, the genomes of two A. baumannii strains were sequenced and were compared genetically in a clinical/medical context; the two strains sequenced were the MDR human clinical isolate AYE responsible for a nationwide outbreak in France in 2003 [15] and the remarkably susceptible strain SDF, which was associated with human body lice [16]. The genome sequence annotation and comparison of both strains allowed the discovery of 52 genes predicted to be associated with resistance to antimicrobial
Habitat and sources
Two types of infection result from A. baumannii, nosocomial and community-acquired infections, implying that there are two types of diseases related to these bacteria and suggesting that there are at least two reservoirs for these bacteria [1]. Whilst A. baumannii is isolated from patients and hospital environmental sources during outbreaks, the reservoir outside of the hospital is not well delineated. Regarding possible sources responsible for nosocomial infections, several investigators have
Resistance mechanisms in Acinetobacter baumannii
Acinetobacter baumannii is intrinsically highly resistant to many antimicrobials, but acquired resistance to other antibiotics has increasingly been reported during the last decade, probably as a consequence of the extensive use of antibiotics in western countries [6] (Fig. 3). The two main definitions of multidrug resistance in A. baumannii are either carbapenem resistance or resistance to more than three classes of antibiotics [33]. Some strains are only susceptible to colistin and
Global epidemiology of Acinetobacter baumannii in Europe
Acinetobacter baumannii outbreaks have been observed in Europe since the early 1980s, notably in France, England, Germany, Spain, Italy and The Netherlands [1], [74]. Investigation of these outbreaks using molecular typing methods demonstrated the relative ease of transmission of this organism between hospitals via transfer of colonised patients [1], [15]. For example, VEB-1 A. baumannii was responsible for interhospital spread in France [15], and the MDR A. baumannii European clone II was
Types of infections
One of the main problems with A. baumannii infections is the definition of infection itself. Acinetobacter baumannii strains are often isolated from respiratory samples and urine specimens obtained from hospitalised patients who are colonised rather than infected [3]. Indeed, it is well known that A. baumannii may be normal inhabitants of the human skin and respiratory tract [3]. Infection due to A. baumannii should be defined as a patient with clinical and biological signs of infection
Clinical impact of Acinetobacter baumannii infections
Because A. baumannii nosocomial infections usually affect critically ill patients who often have both a poor prognosis and co-morbidities, the true clinical impact of this pathogen is still controversial and difficult to assess. A systematic review of matched cohort and case–control studies of mortality attributable to A. baumannii has recently been published and includes six studies with methodological heterogeneities [90]. Overall, mortality of patients attributable to A. baumannii infections
Treatment recommendations and conclusions
Pooled clinical data from this review clearly demonstrate that MDR A. baumannii infections, including those due to carbapenem-resistant strains, are associated with considerable attributable mortality. Although the optimal treatment is not currently well established for MDR A. baumannii infections, the use of colistin alone or in combination for severe infections remains critical. Moreover, the choice of combination should be guided by results of in vitro antibiotic susceptibility testing.
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