Gram negative bacteria - Acinetobacter

What are the key principles of preventing gram negative bacteria – Acinetobacter?

Acinetobacter baumannii is not part of the normal human skin or gut flora and is usually not carried by a previously healthy individual. Rather than being imported from the community, A. baumannii is introduced into the hospital setting by a patient transferred from a healthcare facility where A. baumannii is endemic or epidemic. Resistance to fluoroquinolones and in particular to carbapenems is a surrogate marker for epidemic potential of A. baumannii.

The key principles for infection control of multidrug-resistant A. baumannii in the intensive care unit (ICU) are:

What are the consequences of ignoring control of gram negative bacteria – Acinetobacter?

Ignoring the key infection control concepts listed above may lead to high endemicity of multidrug-resistant A. baumannii, a high incidence of nosocomial transmission, and high rates of ventilator-associated A. baumannii pneumonia and A. baumannii bloodstream infection. Once endemic in an ICU, multidrug-resistant A. baumannii is very difficult to eradicate.

What other information supports the conclusions of research on gram negative bacteria – Acinetobacter, e.g., case-control studies and case series?

There is conclusive evidence that outbreaks of A. baumannii colonization and infection are linked to lack of compliance with infection control practices. In fact, contact precautions have been recommended by the CDC and by the Dutch Working Party on Infection Prevention to prevent the spread of nosocomial A. baumannii. In the absence of clinical trials and case-control studies, the key infection control concepts are based on case series and the information provided by outbreak investigations.

Summary of current controversies.

The clinical impact of nosocomial A. baumannii infection has been a matter of continuing debate. Many studies report high overall mortality rates in patients that have A. baumannii bloodstream infection or pneumonia. However, since A. baumannii mainly affects patients with severe underlying disease, it has been argued that the mortality observed in patients with A. baumannii infections is caused by their underlying disease, rather than as a consequence of A. baumannii infection. Recent evidence, however, indicates that A. baumannii bloodstream infection does have an attributable mortality rate ranging from 8-36%. The impact of airborne transmission of A. baumannii is also not clear and controversy exists if droplet isolation as recommended by the Dutch Working Party on Infection Prevention plays an integral role in controlling outbreaks of A. baumannii in the ICU setting.

What is the impact of gram negative bacteria – Acinetobacter and the need for control relative to infections at other sites or from other specific pathogens?

Acinetobacter spp. have emerged in the past three decades as important nosocomial pathogens associated with a wide range of infections including nosocomial pneumonia and other respiratory tract infections, bloodstream infections, urinary tract infections, meningitis following neurosurgical procedures, burn wound and surgical site infections. There are three different Acinetobacter spp. that make up the vast majority of nosocomial Acinetobacter infections, A. baumannii, A. pittii (previously Acinetobacter genomic species 3), and A. nosocomialis (previously Acinetobacter gen. sp. 13TU). These three species are difficult to differentiate from each other unless molecular methods are applied.

In particular, semiautomated methods for species identification such as VITEK and BD Phoenix are not able to correctly identify these species and usually misidentify A. pittii and A. nosocomialis as A. baumannii. These three species together have been designated the A. baumannii group. A. baumannii accounts for about 60-70% of nosocomial Acinetobacter bloodstream infection, while A. pittii and A. nosocomialis account for 10-20% each. Comparable data regarding species distribution among Acinetobacter spp. involved in ventilator-associated pneumonia and other nosocomial infections are not available. There is now promising data that the wider use of mass spectrometry such as MALDI-ToF for species identification will greatly improve the ability of routine microbiology laboratories to correctly identify acinetobacters to species level.

Members of the genus Acinetobacter, of which more than 30 different species have been described, are generally considered ubiquitous organisms. While this holds true for the majority of Acinetobacter species which can be found regularly in soil and water, on food products such as vegetables, meat and fish, and also as commensals on human skin, A. baumannii does not appear to be an environmental organism. In fact, A. baumannii has evolved into an organism that is perfectly adapted to the hospital environment and the colonized hospital patients as well as contaminated patient-near surfaces serve as the reservoir for nosocomial transmission while the natural habitat of A. baumannii still remains to be defined.

The current situation is characterized by the rapid global emergence of A. baumannii strains resistant to all betalactams including the carbapenems which have until recently been regarded as the drugs of choice for the treatment of A. baumannii infections. Many of these strains are in fact now resistant to all classes of antimicrobials including the aminoglycosides and the fluoroquinolones leaving the polymyxins as the only remaining treatment option. Carbapenem resistance in A. baumannii is mediated most often by oxacillinases (OXAs) and less frequently by metallo-betalactamases (MBLs).

Recent studies have shown that the vast majority of Acinetobacter isolates resistant to the carbapenems are A. baumannii whereas carbapenem resistance in other Acinetobacter spp. including the other members of the A. baumannii group is exceedingly rare. This is one of the reasons why species identification of isolates belonging to the A. baumannii group should be attempted. There are four main OXA subgroups associated with A. baumannii, the chromosomally located intrinsic OXA-51-like and the acquired OXA-23-like, OXA-40-like and OXA-58-like.

Compelling evidence suggests that A. baumannii is clonal in nature. Molecular typing of isolates obtained from various hospitals in Europe has shown the existence of three distinct clusters that have been termed pan-European clonal lineages I, II and III (EU I, II and III, respectively). Isolates belonging to these clonal lineages have been found in nearly all European countries but also outside Europe. More recently it has been shown that these three clonal A. baumannii lineages and further five clonal lineages have spread worldwide and have therefore been designated worldwide or international clonal lineages. In particular, almost 50% of carbapenem-resistant A. baumannii isolates worldwide was shown to belong to the worldwide clonal lineage II (WW2) (corresponding to EU II) indicating global spread of a very successful pathogen.

A. baumannii is notorious for causing hospital outbreaks of infection in particular in severely debilitated patients in the intensive care unit (ICU) setting. Among the factors that contribute to the organisms’ success as nosocomial pathogens are (i) their long-term survival on dry surfaces, (ii) their remarkable ability to up-regulate or acquire resistance mechanisms and making it one of the most difficult-to-treat microorganisms that are often resistant to all available antimicrobials, and (iii) their propensity for epidemic spread. Prolonged skin and pharyngeal carriage of multidrug-resistant A. baumannii among individuals with previous A. baumannii colonization and infection may also contribute to nosocomial spread of this organism.

Other members of the A. baumannii group, A. pittii and in particular A. nosocomialis have also been involved in nosocomial outbreaks but far less frequently than A. baumannii. However owing to the fact that correct species identification has only very rarely been performed in the course of outbreak investigations, the precise role and impact of the latter species still remains to be elucidated. In light of the difficulty to distinguish A. baumannii from A. pittii and A. nosocomialis in clinical microbiology these species will in the following sections be referred to as A. baumannii (in a broader sense) unless stated otherwise.

Numerous potential sources for nosocomial spread of A. baumannii have been identified in the past, including contaminated respiratory therapy equipment, humidifiers, arterial pressure transducers, multi-dose medication vials, mattresses, pillows, bed rails, and more recently computer keyboards and cell phones. Transmission was also found related to specific procedures such as pulsatile lavage wound treatment and hydrotherapy in burn patients. Even airborne transmission has been suggested. Point sources of transmission, however, have not been identified in many recent outbreaks despite an extensive epidemiological work-up (see Table I below).

Table I.

Study	Source/Risk factors	Number of patients involved	Infection control measure instituted
Ray A, 2010	Wounds	13	Reemphasis of standard precautions Contact precautions Vaporized hydrogen peroxide (VHP)
Jung JY, 2010	Mechanical ventilation, invasive devices	200	Active surveillance
La Forgia C, 2010	Sinks, water drainage system	16	Contact isolationEducation of staffEnvironmental screeningDisinfection of entire ICU drainage system with bleach
Jamal W, 2009	No source identified	24	Active surveillanceContact isolationEnvironmental decontamination
Monterrubio-Villar J, 2009	Higher Apache II score	21	Reemphasis of standard precautionsContact isolation/cohortingDisinfection of surfaces with 0.1% hypochlorite
Simmonds A, 2009	No source identified	7	Active surveillanceContact precautionsIsolation/cohortingEducation of staffEnhanced environmental cleaning
Kohlenberg A, 2009	No source identified	32	Active surveillanceContact precautionsIsolation/cohortingEducation of staff
Enoch DA, 2008	No source identified	19	Active surveillanceContact precautionsIsolation/cohortingEducation of staffEnhanced cleaning of environment and equipment with hypochlorite-based agent
Zarilli R, 2007	No source identified	74	Contact precautionsEducation of staffReemphasis of standard precautionsEnhanced cleaning of near-patient objects and surfaces with chlorine
Wybo I, 2007	Patient-to-patient-transmission	28	Active SurveillanceContact precautionsReemphasis of standard precautionsEnhanced cleaning of near-patient objects and surfaces
Lee HC, 2007	Contaminated morphine solution	3	Elimination of contaminated medication
Zanetti G, 2007	Contamination of surfaces in patients’ rooms and the hydrotherapy room	10	Active SurveillanceContact precautions/isolationReemphasis of standard precautionsTemporary closure of wardEnhanced cleaning, disinfection and sterilization of surfaces and equipment before reopening
Young LS, 2007	Therapy with fluconazole and levofloxacin, higher Apache II Score, prolonged mechanical ventilation, chronic pulmonary disease	67	Active SurveillanceContact isolationLimitations of pulsatile lavage wound debridementRemoval of items with upholstered surfacesTerminal cleaning of rooms
De Vegas EZ, 2006	Contaminated parenteral nutrition solution	16	Use of aseptic technique for preparation of nutrition solutionReemphasis of standard precautionsRestriction of antimicrobial
Naas T, 2006	Patient-to-patient-transmission	275	Active surveillanceReemphasis of standard precautionsContact precautionsAppropriate antimicrobial usage
Wilks M, 2006	Widespread environmental contamination including curtains, equipment, cleaned reusable laryngo-scope blades, mops, buckets, door handles, and computer keyboards	136	Education of staffClosed tracheal suctionThorough environmental cleaning and disinfection Reemphasis of standard precautions

An epidemic strain is most commonly introduced by an undetected carrier patient. Once introduced into a ward, the strain can then spread to other patients and their environment. Transmission via the hands of healthcare personnel is likely the most important means of cross-transmission of multi-drug resistant A. baumannii with the colonized patient and contaminated near-patient surfaces serving as the reservoir. Outbreaks involving a single ICU but also multiple ICUs in a single hospital have been described as well as outbreaks involving numerous hospitals in a city or region or even in neighboring countries, most probably via transfer of colonized patients.

Epidemiological typing, mostly by genotypic methods such as pulsed-field gel electrophoresis (PFGE) or PCR-based techniques including rep-PCR and VNTR (variable number of tandem repeats) is an important tool to identify the outbreak strain, to distinguish it from other, concurrent strains and to assess the sources and mode of transmission of this strain. Most recently, two multi locus sequence typing (MLST) schemes have been developed, however while this method is well-suited for the study of the population structure of A. baumannii it is less useful for outbreak delineation.

As with other nosocomial pathogens, various risk factors have been found associated with A. baumannii colonization and infection such as extended hospital stay, severity of illness markers, organ failure, mechanical ventilation, the presence of intravascular access devices, prior antibiotic therapy, and male gender. Since A. baumannii is very rarely introduced into the hospital by a previously healthy carrier, endogenous infection is the exception, and nosocomial exposure is a prerequisite for A. baumannii colonization and infection for most patients. In addition, patient transfer between hospitals or from endemic settings (such as ICUs of high prevalence hospitals) is a major factor contributing to the spread of highly resistant A. baumannii.

There is a striking association between increased rates of nosocomial A. baumannii infections with natural disasters such as the Marmara earthquake that occurred 1999 in Turkey, the 2002 terrorist attack in Bali, the Tsunami disaster in Southeast Asia in 2004, and military operations. A common feature appears to be the sudden incidence of mass casualties that overstress the infection control capacities of local healthcare systems. A high number of deep wound infections, burn wound infections and osteomyelitis has been reported to be associated with repatriated combat casualties of the Iraq and Afghanistan conflicts. Isolates were often multi-drug resistant.

Based on the common misconception that A. baumannii is a ubiquitous organism it has been argued that the organism might have been inoculated at the time of injury either from previously colonized skin or from contaminated soil. However, it is more likely that the soldiers acquired A. baumannii during emergency care and hospitalization in field hospitals. To date, no source has been clearly identified.

Overview of important clinical trials, meta-analyses, case control studies, case series, and individual case reports related to infection control and gram negative bacteria – Acinetobacter.

Table I summarizes the 2005-2010 publications on infection control procedures for the successful control of outbreaks of infections caused by multidrug-resistant A. baumannii.

As with other multidrug-resistant organisms, the mainstay of A. baumannii outbreak containment is education of staff and reinforcement of standard infection control precautions. Given the organisms’ prolonged survival on inanimate surfaces, particular attention should be focused on effective cleaning and disinfection of the environment including equipment used for patient care as well as door handles and computer keyboards.

Active surveillance cultures (respiratory tract samples and rectal or perirectal swabs) of patients with epidemiological links to a patient colonized or infected with multidrug-resistant A. baumannii are required for outbreak control whereas point-prevalence surveys might suffice in the case of endemic A. baumannii occurrence. Patients found colonized or infected with the outbreak strain should be isolated or cohorted and contact precautions should be instituted. Environmental cultures might identify a point source of transmission responsible for the outbreak. Judicious use of effective antimicrobials is advocated although its role among other efforts aimed at outbreak control has not been clearly defined. Vaporized hydrogen peroxide is a newly developed promising tool that has been used effectively for decontamination during an outbreak of multidrug-resistant A. baumannii infection at a long-term acute care hospital. If all these efforts fail to control an ongoing outbreak temporary closure of hospital units or wards may be required.

Controversies in detail.

No studies have directly compared the efficacy of standard precautions alone versus standard precautions and contact precautions, with or without active surveillance cultures (ASC), for controlling multidrug-resistant A. baumannii. Some researchers have used one or both sets of precautions as part of their successful outbreak control efforts (see table above); however, the precautions were not the primary focus of the study intervention.

What national and international guidelines exist related to gram negative bacteria – Acinetobacter?

The Dutch Working Party on Infection Prevention has issued guidelines for preventing nosocomial transmission of highly resistant microorganisms (HRMO) that include Acinetobacter spp. Highly resistant Acinetobacter spp. was defined as isolates resistant against carbapenems or against antibacterial agents from at least two of the groups’ ceftazidime, fluoroquinolones and aminoglycosides.

The CDC has published strategies outlined in the 2006 HICPAC guidelines for the management of multidrug-resistant organisms (MDRO) in healthcare settings without specifically addressing multidrug-resistant A. baumannii defined herein as A. baumannii resistant to all antimicrobials or to all antimicrobials except imipenem. More recently, the CDC and HICPAC published guidance for control of infections with carbapenem-resistant or carbapenemase-producing Enterobacteriaceae that may also be applied to the control of infections caused by carbapenem-resistant A. baumannii but have never specifically addressed infection control in Acinetobacter spp.

No other national or international guidelines have been published that address this issue.

References

Management of multidrug-resistant organisms in healthcare settings, 2006. 2007.

Kluytmans-Vandenbergh, MF, Kluytmans, JA, Voss, A. “Dutch guideline for preventing nosocomial transmission of highly resistant microorganisms (HRMO)”. Infection. vol. 33. 2005. pp. 309-13.

Peleg, AY, Seifert, H, Paterson, DL. “Acinetobacter baumannii: emergence of a successful pathogen”. Clin Microbiol Rev. vol. 21. 2008. pp. 538-82.

Dijkshoorn, L, Nemec, A, Seifert, H. “An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii”. Nat Rev Microbiol. vol. 5. 2007. pp. 939-51.

Nemec, A, Krízová, L, Maixnerová, M, Diancourt, L, van der Reijden, TJ, Brisse, S, van den Broek, P, Dijkshoorn, L. “Emergence of carbapenem resistance in Acinetobacter baumannii in the Czech Republic is associated with the spread of multidrug-resistant strains of European clone II”. J Antimicrob Chemother. vol. 62. 2008. pp. 484-9.

Higgins, PG, Dammhayn, C, Hackel, M, Seifert, H. “Global spread of carbapenem-resistant Acinetobacter baumannii”. J Antimicrob Chemother. vol. 65. 2010. pp. 233-8.

Karageorgopoulos, DE, Falagas, ME. “Current control and treatment of multidrug-resistant Acinetobacter baumannii infections”. Lancet Infect Dis. vol. 8. 2008. pp. 751-62.

Jawad, A, Seifert, H, Snelling, AM, Heritage, J, Hawkey, PM. “Survival of Acinetobacter baumannii on dry surfaces: comparison of outbreak and sporadic isolates”. J Clin Microbiol. vol. 36. 1998. pp. 1938-41.

Marchaim, D, Navon-Venezia, S, Schwartz, D, Tarabeia, J, Fefer, I, Schwaber, MJ, Carmeli, Y. “Surveillance cultures and duration of carriage of multidrug-resistant Acinetobacter baumannii”. J Clin Microbiol. vol. 45. 2007. pp. 1551-5.

Naas, T, Coignard, B, Carbonne, A, Blanckaert, K, Bajolet, O, Bernet, C, Verdeil, X, Astagneau, P, Desenclos, JC, Nordmann, P. “French Nosocomial Infection Early Warning Investigation and Surveillance Network. VEB-1 Extended-spectrum beta-lactamase-producing Acinetobacter baumannii, France”. Emerg Infect Dis. vol. 12. 2006. pp. 1214-22.

Bartual, SG, Seifert, H, Hippler, C, Luzon, MA, Wisplinghoff, H, Rodríguez-Valera, F. “Development of a multilocus sequence typing scheme for characterization of clinical isolates of Acinetobacter baumannii”. J Clin Microbiol. vol. 43. 2005. pp. 4382-90.

Diancourt, L, Passet, V, Nemec, A, Dijkshoorn, L, Brisse, S. “The population structure of Acinetobacter baumannii: expanding multiresistant clones from an ancestral susceptible genetic pool”. PLoS One. vol. 5. 2010 . pp. e10034

Davis, KA, Moran, KA, McAllister, CK, Gray, PJ. “Multidrug-resistant Acinetobacter extremity infections in soldiers”. Emerg Infect Dis. vol. 11. 2005. pp. 1218-24.

Falagas, ME, Thomaidis, PC, Kotsantis, IK, Sgouros, K, Samonis, G, Karageorgopoulos, DE. “Airborne hydrogen peroxide for disinfection of the hospital environment and infection control: a systematic review”. J Hosp Infect. vol. 78. 2011. pp. 171-7.

Ray, A, Perez, F, Beltramini, AM, Jakubowycz, M, Dimick, P, Jacobs, MR, Roman, K, Bonomo, RA, Salata, RA. “Use of vaporized hydrogen peroxide decontamination during an outbreak of multidrug-resistant Acinetobacter baumannii infection at a long-term acute care hospital”. Infect Control Hosp Epidemiol. vol. 31. 2010. pp. 1236-41.

Jung, JY, Park, MS, Kim, SE, Park, BH, Son, JY, Kim, EY, Lim, JE, Lee, SK, Lee, SH, Lee, KJ, Kang, YA, Kim, SK, Chang, J, Kim, YS. “Risk factors for multi-drug resistant Acinetobacter baumannii bacteremia in patients with colonization in the intensive care unit”. BMC Infect Dis. vol. 10. 2010. pp. 228

La Forgia, C, Franke, J, Hacek, DM, Thomson, RB, Robicsek, A, Peterson, LR. “Management of a multidrug-resistant Acinetobacter baumannii outbreak in an intensive care unit using novel environmental disinfection: a 38-month report”. Am J Infect Control. vol. 38. 2010. pp. 259-63.

Jamal, W, Salama, M, Dehrab, N, Al Hashem, G, Shahin, M, Rotimi, VO. “Role of tigecycline in the control of a carbapenem-resistant Acinetobacter baumannii outbreak in an intensive care unit”. J Hosp Infect. vol. 72. 2009. pp. 234-42.

Monterrubio-Villar, J, González-Velasco, C, Valdezate-Ramos, S, Córdoba-López, A, Villalón-Panzano, P, Saéz-Nieto, JA. “Outbreak of multiresistant Acinetobacter baumannii in a polyvalent intensive care unit: clinical, epidemiological analysis and PFGE-printing evolution”. Eur J Clin Microbiol Infect Dis. vol. 28. 2009. pp. 1281-4.

Simmonds, A, Munoz, J, Aguero-Rosenfeld, M, Carbonaro, C, Montecalvo, M, Clones, B, LaGamma, EF. “Outbreak of Acinetobacter infection in extremely low birth weight neonates”. Pediatr Infect Dis J. vol. 28. 2009. pp. 210-4.

Kohlenberg, A, Brümmer, S, Higgins, PG, Sohr, D, Piening, BC, de Grahl, C, Halle, E, Rüden, H, Seifert, H. “Outbreak of carbapenem-resistant Acinetobacter baumannii carrying the carbapenemase OXA-23 in a German university medical centre”. J Med Microbiol. vol. 58. 2009. pp. 1499-507.

Enoch, DA, Summers, C, Brown, NM, Moore, L, Gillham, MI, Burnstein, RM, Thaxter, R, Enoch, LM, Matta, B, Sule, O. “Investigation and management of an outbreak of multidrug-carbapenem-resistant Acinetobacter baumannii in Cambridge, UK”. J Hosp Infect. vol. 70. 2008. pp. 109-18.

Zarrilli, R, Casillo, R, Di Popolo, A, Tripodi, MF, Bagattini, M, Cuccurullo, S, Crivaro, V, Ragone, E, Mattei, A, Galdieri, N, Triassi, M, Utili, R. “Molecular epidemiology of a clonal outbreak of multidrug-resistant Acinetobacter baumannii in a university hospital in Italy”. Clin Microbiol Infect. vol. 13. 2007. pp. 481-9.

Wybo, I, Blommaert, L, De Beer, T, Soetens, O, De Regt, J, Lacor, P, Piérard, D, Lauwers, S. “Outbreak of multidrug-resistant Acinetobacter baumannii in a Belgian university hospital after transfer of patients from Greece”. J Hosp Infect. vol. 67. 2007. pp. 374-80.

Lee, HC, Lee, NY, Chang, CM, Chou, CY, Wu, YH, Wang, LR, Ko, NY, Liu, CC, Ko, WC. “Outbreak of Acinetobacter baumannii bacteremia related to contaminated morphine used for patient-controlled analgesia”. Infect Control Hosp Epidemiol. vol. 28. 2007. pp. 1213-7.

Zanetti, G, Blanc, DS, Federli, I, Raffoul, W, Petignat, C, Maravic, P, Francioli, P, Berger, MM. “Importation of Acinetobacter baumannii into a burn unit: a recurrent outbreak of infection associated with widespread environmental contamination”. Infect Control Hosp Epidemiol. vol. 28. 2007. pp. 723-5.

Young, LS, Sabel, AL, Price, CS. “Epidemiologic, clinical, and economic evaluation of an outbreak of clonal multidrug-resistant Acinetobacter baumannii infection in a surgical intensive care unit”. Infect Control Hosp Epidemiol. vol. 28. 2007. pp. 1247-54.

De Vegas, EZ, Nieves, B, Araque, M, Velasco, E, Ruiz, J, Vila, J. “Outbreak of infection with Acinetobacter strain RUH 1139 in an intensive care unit”. Infect Control Hosp Epidemiol. vol. 27. 2006. pp. 397-403.

Wilks, M, Wilson, A, Warwick, S, Price, E, Kennedy, D, Ely, A, Millar, MR. “Control of an outbreak of multidrug-resistant Acinetobacter baumannii-calcoaceticus colonization and infection in an intensive care unit (ICU) without closing the ICU or placing patients in isolation”. Infect Control Hosp Epidemiol. vol. 27. 2006. pp. 654-8.

“Guidance for control of infections with carbapenem-resistant or carbapenemase-producing Enterobacteriaceae in acute care facilities”. MMWR Morb Mortal Wkly Rep. vol. 58. 2009. pp. 256-60.

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