Jul 1, 2011 - giene of the staff leads to cross transmission of the cau- sative organism to .... corded in a prospective database (Microsoft Excel): gen- der, age, total length of ..... MATERIJAL I METODE: Prospektivnom ko- hortnom studijom ...
UDK 616.33-002-093-06 DOI:10.2298/ACI1104081M
/STRU^NI RAD
Acinetobacter spp. colonization and infection risk factors in surgical patients ........ .................................
rezime
Vesna Mioljevi}2, Aleksandar P. Simi}1,3, Dejan Radenkovi}1,3,Danijel Galun3, Ivan Palibrk1,3, Slavenko Ostoji}1, Dejan Stojakov1,3, Zorica Varagi}5, Milorad Pavlovi}1,4, Miroslav N. Mili}evi}1,3 1 Faculty of Medicine, University of Belgrade, Serbia 2 Department of hospital epidemiology and hygiene, Clinical Center of Serbia, 3 Clinic of Digestive Surgery, Clinical Center of Serbia, Belgrade 4 Clinic of infectious disease, Clinical Center of Serbia, Belgrade 5 Department of Microbiology, Clinical Center of Serbia, Belgrade
INTRODUCTION: The results of numerous studies carried out over the last two decades have indicated that Acinetobacter spp. represents an increasingly important cause of intrahospital infections (IHI). The aim of the study was to determine potential differences in distribution of individual risk factors between the group of patients in whom multiresistant Acinetobacter spp. was isolated and the group of patients in whom it was not. MATERIAL AND METHODS: A prospective cohort study of 64 patients hospitalized with recorded IHI at the University Hospital for Digestive Surgery, Clinical Center of Serbia in the period between January and July 2011. The subjects were divided into two groups: patients with IHI in whom multiresistant Acinetobacter spp. was isolated from the biological material samples, and those with IHI without the presence of Acinetobacter spp. RESULTS: Univariate data analysis indicated presence of statistically significant difference in distribution of certain types of surgeries (esophageal, pancreatic and hepatobiliary) among the two groups of subjects, distribution of CVC placement, application of mechanical ventilation and nasogastric tube placement, length of stay in ICU, lethal outcomes and administration of third generation cephalosporins. The results of multivariate analysis indicated that length of hospitalization in ICU (> 7 days), CVC, mechanical ventilation, esophageal, pancreatic and hepatobiliary surgeries as well as administration of third generation cephalosporins are independent risk factors for colonization and infection of patients with Acinetobacter spp. CONCLUSION: Colonized or infected patients with Acinetobacter spp. play a major role in contamination of hands of the medical staff in the course of care and treatment, while inadequate hand hygiene of the staff leads to cross transmission of the causative organism to infection-free patients. Selective an-
tibiotic pressure, particularly administration of quinolones and broad-spectrum cephalosporins, favor onset of multiresistant species of Acinetobacter spp., and therefore appropriate prophylaxis and treatment represent basic preventive measures against the onset and spreading of the causative organisms. Key words: Acinetobacter spp., intrahospital infection, resistance, prevention INTRODUCTION:
T
he results of numerous studies carried out over the last two decades have indicated that Acinetobacter spp. represents an increasingly important cause of intrahospital infections (IHI).1 The significance of the nosocomial pathogen is primarily reflected in its increasingly frequent isolation from different samples (wound smear, blood, urine, bronchial aspirate), as well as resistance of Acinetobacter spp. to numerous antibiotics. Growing numbers of Acinetobacter spp. strains are multi drug resistance (MDR), thereby limiting therapeutic options. 2,3 The risk factors for Acinetobacter spp. colonization and infection include: hospitalization at the intensive care units (ICU), burn treatment and neonatology departments, length of hospitalization, application of artificial ventilation, surgical interventions, immunosuppression as well as administration of broad-spectrum antibiotics.1,4,5,6 In 25% of adult healthy individuals Acinetobacter spp. may be a part of the physiological skin flora (particularly in the armpit and groins). Colonization rates of the oral cavity and upper airway with this causative organism are significantly higher among the hospitalized patients, particularly in those on mechanical ventilation. Digestive tract colonization with Acinetobacter spp. is considered to be uncommon, although it has been documented in several studies that digestive tract may also be a significant reservoir of the causative organism in the hospitalized patients. Acinetobacter spp. most commonly causes IHI of
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the surgical site (SSI), infections of the respiratory (IRT) and urinary (IUT) tracts.7,8 Colonized or infected patients play major role in contamination of hands of the medical staff in the course of care and treatment, while inappropriate hand hygiene of the staff leads to the cross transmission of the causative organism to the non-colonized patients.9,10 Numerous studies have also indicated significance of environmental contamination in hospitals with Acinetobacter spp., particularly in the parts of the mechanical ventilation system, air and patient’s immediate environment. A case of contamination of hospital environment with multiresistant Acinetobacter spp. two weeks after patient’s discharge has also been documented.11,12 Growing numbers of Acinetobacter spp. strains are multi drug resistant (MDR), thereby limiting therapeutic options. Selective antibiotic pressure, particularly administration of quinolones and broad-spectrum cephalosporins favor development of multiresistant species of Acinetobacter spp. and therefore, correct antibiotic prophylaxis and treatment represent basic preventive measures against the onset and spreading of the causative organisms1,13,14,15 The aim of this prospective study was to determine possible differences in distribution of individual risk factors between the group of patients in whom multiresistant Acinetobacter spp. was isolated and group of patients in whom it was not. MATERIAL AND METHODS A prospective cohort study included 64 patients hospitalized at the University Hospital for Digestive Surgery, Clinical Center of Serbia in the period January 1st, 2011 July 1st, 2011 with recorded IHI (SSI, IUT, Blood steam Infection (BSI). IHI were recorded based on the relevant definitions16. Review of patient histories, interview with medical staff and patients provided registration of all necessary information for the study. The information was entered into questionnaire for each individual patient. The subjects were divided in two groups: group 1 included 21 patients with IHI in whom multiresistant Acinetobacter spp. was isolated from the biological material samples, while group 2 comprised of 43 patients with IHI in whom multiresistant Acinetobacter spp. was not isolated. The following features related to patient, diagnostic and therapeutic procedures to which they were exposed are recorded in a prospective database (Microsoft Excel): gender, age, total length of stay, length of stay at the ICU, underlying disease, type of surgery, placement of CVC and urinary catheters, presence of nasogastric tube, drainage, mechanic ventilation, antibiotic treatment (type of antibiotic) before the day of Acinetobacter spp. isolation.1,4,5 Isolation and identification of Acinetobacter spp. was performed using standard microbiological methods, while Gram preparation and biochemical properties, and isolate susceptibility were determined based on CLSI standards.17 Methods of descriptive and analytical statistics (methods for assessment of significance of differences: Student’s t test and X2 test) were used in the study. Statistical data
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TABLE 1 NUMBER OF PATIENTS WITH ISOLATED ACINETOBACTER SPP. ACCORDING TO TYPE OF SAMPLE Type of sample
No (%) of patients with Acinetobacter spp (n=21)
Wound smear
7 (26%)
BAL*
7 (26%)
Drain contents
7 (26%)
Hemoculture
4 (19%)
CVC**
2 (1%)
*BAL- bronchoalveolar lavage; **Central Venous Catheter
analysis were performed using SPSS (version 10) software. RESULTS Out of the total number of 64 hospitalized patients with registered IHI, multiresistent Acinetobacter sppwas isolated from different biological material samples in 33% of cases (21 patients). Out of those patients a total of 27 isolates of Acinetobacter spp were isolated from the biological material samples (wound smear, hemoculture, bronchial aspirate (BAL), CVC, drain contents). (Table 1) Analyzing susceptibility of Acinetobacter spp. to antibiotics, three resistotypes were evidenced in our study: sensitive to netilmicin., ampicilin and amicacin/gentamicin,, sensitive to tigecycline and ampicillin-sulbactam and colistin-only sensitive Univariate data analysis indicated presence of statistically significant difference in distribution of certain types of surgical procedures (esophageal, pancreatic and hepatobiliary) among the two groups of subjects: esophageal (OR%:1.1; 95%CI:1.17-1.41; p=0.011); pancreatic (OR% :1.1; 95%CI:1.18-1.41; p=0.011); hepatobiliary (OR%:3; 95%CI:1.28-1.56; p=0.018). As for the group of subjects with Acinetobacter spp. isolates, 14(66%) patients were hospitalized at ICU for more than 7 days in comparison to 9(10%) from the second group of patients, which indicated a statistically significant difference (OR% :1.1%, 95%CI:1.04-1.19; p= 0.002) (Table 2). Statistically significant difference was also evidenced in comparison of CVC placement, application of mechanical ventilation and nasogastric tube placement between the groups: CVC (OR%:5.8; 95%CI:1.19-28.5; p=0.018), mechanical ventilation (OR%:4.0; 95%CI:1.09-1.37; p=0.0121), nasogastric tube (OR%:5; 95%CI:1.04-1.33; p=0.003) (Table 2). As for the group of subjects with Acinetobacter spp. isolates, lethal outcomes were evidenced in 9 (41%) in comparison to 11 (25%) patients in the second group, which was proved to be statistically significantly differ-
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TABLE 2 CHARACTERISTICS OF PATIENTS WITH ADN WITHOUT ACINETOBACTER SPP ACCORDING TO UNIVARIATE ANALYSIS With Acinetobacter spp (n=21)
Without Acinetobacter spp (n=43)
OR (95% CI)
P
Age (mean/+/-SD)
61.4/11.4
59/12.6
1.00 (1.63-1.98)
0.175
Sex (male/female)
16/5
23/20
2.64 (1.01-1.40)
0.090
Esophageal surgery
2*/19
0/43
1.1 (1.17-1.41)
0.011
Gastric surgery
3/18
09./34
1.4 (1.21-1.48)
0.530
Pancreatic surgery
3/18
0/43
1.1 (1.18-1.41)
0.011
Hepatobiliary surgery
4/17
19/24
3( 1.28-1.56)
0.018
Colorectal surgery
3/18
8/35
1.1( 1.20-1.56)
0.840
Herniation surgery
3/18
3/40
2.6 (1.19-1.44)
0.354
Other
1/20
3/40
1.5 (1.12-1.45)
0.736
Lenght of stay in ICU* >10 days
14/7
9/36
1.1( 1.04-1.19)
0.002
Central venou8s cahtehter (yes/no)
19/3
26/19
5.8 (1.19-28.5)
0.018
Bladder catheter (yes/no)
11/10
36/7
1.5( 0.29-8.61)
0.600
Comorbidity (yes/no)
5/16
9/36
1 (0.26-0.32)
0.834
Mechanical ventilation (yes/no)
11/10
9/36
4 (1.09-1.37)
0.012
Nasogastric tube (yes/no)
12/9
14/27
5( 1.04-1.33)
0.003
Mortality (yes/no)
9/21
11/32
4 (1.30-12.40)
0.012
Surgeries
*ICU - Intencive Care unit; c-number of patients
ence based on the univariate analysis (OR%:4.0; 95%CI:1.30-1.24; p=0.012) (Table 2). Statistically significant difference was also evidenced with respect to administration of antibiotics from the group of 3rd generation cephalosporins (OR%:4.0; 95%CI:1.19-1.44; p=0.013) between the groups with and without Acinetobacter spp. isolates . Univariate data analysis did not reveal statistically significant difference between the two groups with respect to gender, age, placement of urinary catheter, comorbidity, gastric and colon surgeries as well as with respect to administration of cephalosporin antibiotics of the first and second generation, carbapenem, aminoglycosides and, antianaerobic medicines. (Table 3) The results of multivariate analysis evidenced that length of hospitalization in ICU (longer than 7 days), CVC, mechanical ventilation, esophageal, hepatobiliary surgeries as well as administration of third generation cephalosporins are independent risk factors for colonization and infection of patients with Acinetobacter spp. (Table 4).
DISCUSSION Multidrug-resistant Acinetobacter spp. is a rapidly emerging pathogen in the health care setting. The organism’s ability to survive under a wide range of environmental conditions and to persist for extended periods of time on surfaces makes it a frequent cause of outbreaks of infection and an endemic, healthcare-associated pathogen7. Susceptible patients include those who have recently undergone major surgery, those with severe underlying disease (e.g., malignancy, burns or immunosuppression), critically ill patients in ICUs)8. In their studies of risk factors for Acinetobacter spp. colonization and infection, Koeleman and Jang did not observe statistically significant difference in frequency of Acinetobacter spp. isolation with respect to gender and age18,19. The former is consistent with the results obtained in our study, in which no gender and age-related statistically significant differences were evidenced between the two groups of subjects (Table 2).
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TABLE 3 ANTIBIOTIC USE: PATIENTS WITH AND WITHOUT ACINETOBACTER SPP. ACCORDING TO UNIVARIATE ANALYSIS No % of patients Without With Acinetobacter spp Acinetobactger spp ((43) (n=21)
Cephalospsints (1st generation)
OR (95% CI)
P
0/21
3/39
1.2 (1.22-1.47)
0.216
0/21
5/37
1.3 (1.23-1.48)
0.103
Cephalosporins (3 genration)
15/6
16/27
4.0( 1.02-1.34)
0.013
Carbapenems
10/11
14/29
2.0 (1.12-1.42)
0.201
Aminoglycosides
3/18
6/37
1.1 (1.19-1.45)
0.793
Antianaerobic agents
11/10
16/27
1.5 (1.11-1.42)
0.212
Glycopeptides
3/18
5/38
1.1 (1.19-1.45)
0.793
Quinolones
2/19
2/43
1.0 (1.19-1.44)
0.473
nd
Cefaphsporins (2 generations) rd
Univariate analysis revealed in our series statistically significant differences between the two groups of subjects related to certain types of surgeries (esophageal, pancreatic and hepatobiliary system surgeries). Presence of statistically significant difference between the two groups of subjects with respect to type of surgery may be explained by severity of the underlying disease and length of hospitalization of these patients at ICU. Large number of studies evidenced that length of hospitalization at ICU is an important risk factor for Acinetobacter spp. colonization and infection8,18,19,20,21. Ayats evidenced in their study that out of 73 patients hospitalized at ICUs, 48(66%) were colonized with Acinetobacter spp. (axillary, pharyngeal or rectal colonization). Out of 48 colonized patients, 9(19%) were colonized during the first week, while 28 (77%) were colonized during the second week of hospitalization22. In our study, in the group of subjects with Acinetobacter spp. isolates, 14(66%) patients were hospitalized at ICU for more then 7 days in comparison to 9(10%) patients from the second study group, which makes a statistically significant difference (Table 2). Statistically significant difference was also evidenced in frequency of CVC placement, application of mechanical ventilation and nasogastric tubein the group of subjects with Acinetobacter spp. isolates in comparison to the group in which the causative organism was not isolated (Table 2). Results of other studies of the most important risk factors for Acinetobacter spp. olonization and infection revealed similar results. Back-Sague et al. evidenced in their study on 73 patients from 5 ICUs from New Jersey (USA) hospitals that mechanical ventilation and application of intravascular catheters are independent risk factors for development of bacteriemias caused by Acinetobacter spp.23. Gruper stressed in the results of his study that me-
chanical ventilation and CVC application are risk factors for onset of BSI caused by Acinetobacter spp.24. As for our studied group of patients with Acinetobacter spp. isolates, lethal outcomes were registered in 9(41%) patients, in comparison to 11(25%) cases in the second studied group. Univariate analysis revealed that the difference was statistically significant (Table 2), while multivariate analysis failed to evidence statistically significant difference in number of lethal outcomes between the two groups of subjects (Table .3). Acinetobacter spp. is resistant to a large number of antibiotics (penicillins/ß-lactamase inhibitors, cephalosporins, aminoglycosides, fluoroquinolones and carbapenems), with varying mechanisms of resistance (selection, mutation, selective antibiotic pressure)15,25 In one study in the UK, the antimicrobial susceptibility of Acinetobacter spp. obtained from clinical specimens in 54 laboratories was investigated. The majority of the isolates were found to be more resistant to cefotaxime, ceftazidime, piperacillin, piperacillin + tazobactam, gentamicin26. Guillou et al. screened 100 isolates of Acinetobacter spp. and found that 81% of the strains produced two types of ß-lactamases (TEM and CARB)27. Analyzing susceptibility of Acinetobacter spp. to antibiotics, three resistotypes were evidenced in our study: sensitive to netilmicin, ampicilin and amicacin/gentamicin, sensitive to tigecycline and ampicillin-sulbactam and colistin-only sensitive. Based on the results of analyses of several studies, it was observed that selective antibiotic pressure, primarily carbapenem and third generation cephalosporins, favors onset and selection of the multiresistants species28,29. Conversely, results of similar studies failed to evidence association between administration of the two antibiotic classes and onset of the multiresistant species30.
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TABLE 4 RISK FACTOR FOR ACINETOBACTER SPP COLONIZATION AND INFECTION ACCORDING TO MULTIVARIATE LOGISTIC REGRESSION ANALYSIS B
S.E
OR (95%CI)
P[
Lenght of stay in ICU >10 days
0.241
0.048
1.5 (0.04-0.52)
0.001
Central Venous Catheter
0.284
0.512
5.8 (0.33-0.68)
0.001
Mechanical ventilation
0.693
0.267
2.3 (1.15-2.64)
0.013
Esophageal surgery
0.737
0.138
5.3 (0.46-1.01)
0.001
Hepatobiliary surgery
0.470
0.104
4.5 (0.67-0.26)
0.001
0.425
0.131
4.5 (0.67-0.26)
0.001
rd
Cephalosporins (3 generation)
Results of our study evidence that in the group of colonized patients, before isolation of multiresistant Acinetobacter spp Acinetobacter spp., 15(71%) patients received third generation cephalosporins, in comparison to14(33%) patients from the group two, which makes statistically significant difference (Table 3). Univariate analysis failed to observe statistically significant differences between the two groups of subjects related to administration of cephalosporin group antibiotics if the first and second generations, carbapenem, aminoglycosides and antianaerobic medicines (Table 3). The results of multivariate analysis show that length of hospitalization at ICU (longer than 7 days), CVC, mechanical ventilation, esophageal, hepatobiliary system surgeries as well as administration of third generation cephalosporins are independent risk factors for colonization and infection of patients with Acinetobacter spp. (Table 4). Acinetobacter spp. represents increasingly important hospital pathogen, and its significance is primarily reflected in increasingly frequent isolation, resistance to large number of antibiotics and problems associated with treatment of infections caused by this multiresistant causative organism. Risk factors for colonization and infection with Acinetobacter spp. include: hospitalization at the intensive care units (ICU), length of hospitalization, application of mechanical ventilation, surgical interventions, immunosuppression as well as administration of broad-spectrum antibiotics. Colonized or infected patients play a major role in contamination of hands of the medical staff in the course of care and treatment, while inadequate hand hygiene of the staff leads to cross transmission of the causative organism to infection-free patients. Additionally, significance of the causative organism for etiology of intrahospital infections is also reflected in contamination of hospital setting with Acinetobacter spp., particularly parts of the mechanical ventilation apparatus, air and immediate environment of the patients. Selective antibiotic pressure, particularly administration of quinolones and broad-spectrum cephalosporins, favor onset of multiresistant species of Acinetobacter spp. and thus, appropriate prophylaxis and treatment represent basic preventive measures against onset and spreading of the causative organism .
SUMMARY ACINETOBACTER SPP. - FAKTORI RIZIKA ZA KOLONIZACIJU I INFEKCIJU KOD HIRUR[KIH BOLESNIKA UVOD: Faktori rizika za kolonizaciju i infekciju Acinetobacter spp. su: hospitalizacija na odeljenjima intenzivne nege (ION), odeljenjima za le~enje opekotina i neonatologije, du‘ina hospitalizacije, primena mehani~ke ventilacije, hirur{ke intervencije, imunosupresija kao i primena antibiotika {irokog spektra. Cilj rada je da se utvrdi da li postoji razlika u zastupljenosti pojedinih faktora rizika u grupi pacijenata koji su kolonizovani ili inficirani Acinetobacter spp. i grupe pacijenata koji nisu kolonizovali ili inficirani. MATERIJAL I METODE: Prospektivnom kohortnom studijom obuhva}ena su 64 pacijenta hospitalizovana na Klinici za digestivnu hirurgiju u periodu od 01.01. do 01.07.2011.godine. Ispitanici su podeljeni u dve grupe: prva grupa - pacijenti sa BI kod kojih je izolovan multirezistentni Acinetobacter spp.; druga grupa - pacijenti sa BI kod kojih nije izolovan multirezistentni Acinetobacter spp. REZULTATI: Univarinantna analiza pokazala je postojanje statisti~ki zna~ajne razzlike izmedju dve grupe ispitanika u odnosu na pojedine vrste operacija (operacije jednjaka, pankreasa i hepatobilijarnog sistema), du‘ine hospitalizacije na OIN, plasiranje CVK, nazogastri~ne sonde, primene mehani~ke ventilacije, broja smrtnih ishoda i primene tre}e generacije cefalosporina. Rezultati multivarijantne analize pokazuju su da su du‘ina hospitalizacije u ICU (du‘a od 7 dana), CVC, mehani~ka ventilacija, operacije jednjaka, pankreasa i hepatobilijarnog sistema kao i primena cefalosporina tre}e generacije nezavisni faktori rizika za kolonizaciju i infekciju pacijenata Acinetobacter spp. ZAKLJU^AK: Kolonizovani ili inficirani pacijenti imaju va‘nu ulogu u kontaminaciji ruku medicinskog osoblja u toku nege i terapije, a neadekvatna higijena ruku osoblja dobodi do preno{enja i {irenja (cross transmission) ovog uzro~nika na nekolonizovane pacijente. Osim toga, zna~aj ovog uzro~nika u etiologiji bolni~kih infekcija ogleda se u kontaminaciji bolni~ke sredine Acinetobacter spp., posebno delova aparata
86
V. Mioljevi} et al.
za mehani~ku ventilaciju, vazduha i neposredne okoline pacijenta. Selektivni pritisak antibiotika, posebno primena hinolona i cefalosporina {irokog spektra, favorizuju nastanak multirezistentnih sojeva Acinetobacter spp. te je stoga jedna od osnovnih mera prevencije nastanka i {irenja ovog uzro~nika pravilna antibiotska profilaksa i terapija. Klju~ne re~i: Acinetobacter spp, bolni~ke infekcije, rezistencija, prevencija REFERENCES 1. Jamal W, Salama M, Dehrab N, Al Hashem G, Shahin M, Rotimi V.O. Role of tigecycline in the control of a carbapenem resistant Acinetobacter baumannii outbreak in an intensive care unit. Journal of Hospital Infection 2009; 72: 234-242. 2. ON JY, Kim KS, Jeong YW, Cho JW, Park JC, Lee JC. Epidemiological typing and prevalence of integrons in multiresistant Acinetobacter strains. APMIS 2002; 110: 247-252. 3. Van Dessel H, Dijkshoorn L, van der Reijden T, Bakker N, Paauw A, van den Broek P, Verhoef J, Brisse S. Identification of a new geographically widespread multiresistant Acinetobacter baumannii clone from European hospitals. Res Microbiol 2004; 155: 105-112. 4. Grupper M, Sprecher H, Mashiach T, Finkelstein R.Attributable mortality of nosocomial Acinetobacter bacteremia. Infect Control Hosp Epidemiol 2007;28:293298. 5. Valles J, Leon C, Alvarez-Lerma F, et al. Nosocomial bacteremiain critically ill patients: a multi-center study evaluating epidemiology and prognosis. Clin Infect Dis 1997; 24: 387-395. 6. Gales AC, Jones RN, Sader HS. Global assessment of the antimicrobial activity of polymyxin B against 54 731 clinical isolates of gram-negative bacilli: report from the SENTRY antimicrobial surveillance programme. (20012004). Clin Microbiol Infect 2006; 12: 315-21. 7. Fournier E, Richet H.. The epidemiology and control of Acinetobacter baumannii in health care facilities. Clin Infect Dis 2006; 42: 692-699. 8. Peleg, AY, Seifert H, Paterson DL. Acinetobacter baumannii: emergence of a successful pathogen. Clin Microbiol Rev 2008; 21: 538-582. 9. Pittet D, Allegranzi B , Sax H , Dharan S , PessoaSilva CL , Donaldson L, Boyce JM. WHO Global Patient Safety Challenge, World Alliance for Patient Safety. Evidence-based model for hand transmission during patient care and the role of improved practices. 2006; 6; 641-652. 10. Getchell-White SI, Donowitz LG, Groschel DH. The inanimate environment of an intensive care unit as a potential source of nosocomial bacteria: evidence for long survival of Acinetobacter calcoaceticus. Infect Control Hosp Epidemiol 1989; 10: 402-407. 11. Gaynes R, Edwards JR. Overview of nosocomial infections caused by Gram-negative bacilli. Clin Infect Dis 2005; 41: 848-854. 12. Maragakis LL, Perl TM. Acinetobacter baumannii: epidemiology, antimicrobial resistance, and treatment options. Clin Infect Dis 2008; 46: 1254-1263..
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