Bacteremic nosocomial pneumonia caused by Acinetobacter baumannii and Acinetobacter nosocomialis: a single or two distinct clinical entities?

ORIGINAL ARTICLE INFECTIOUS DISEASES Bacteremic nosocomial pneumonia caused by Acinetobacter baumannii and Acinetobacter nosocomialis: a single or two distinct clinical entities? Y.-T. Lee 1,2,3, S.-C. Kuo 1,4, S.-P. Yang 2,5, Y.-T. Lin 1,2,5, D.-H. Chiang 2,6, F.-C. Tseng 4, T.-L. Chen 1,2,5 and C.-P. Fung 1,2,5 1) Institute of Clinical Medicine, 2) School of Medicine, National Yang-Ming University, Taipei, 3) Department of Medicine, Chutung Veterans Hospital, Hsinchu County, 4) National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County, 5) Division of Infectious Diseases and 6) Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Abstract The phenotypically indistinguishable Acinetobacter baumannii and Acinetobacter nosocomialis have become leading pathogens causing nosocomial pneumonia in critically ill patients. A. baumannii and A. nosocomialis nosocomial pneumonias were grouped as a single clinical entity previously. This study aimed to determine whether they are the same or a different clinical entity. A total of 121 patients with A. baumannii and 131 with A. nosocomialis bacteremic nosocomial pneumonia were included during an 8-year period. Despite the similar Charlson co-morbidity scores at admission, patients with A. baumannii pneumonia were more likely to have abnormal haematological findings, lobar pneumonia, significantly higher Acute Physiology and Chronic Health Evaluation II scores and higher frequency of shock at the onset of bacteraemia than those with A. nosocomialis pneumoni. A. baumannii isolates were resistant to more classes of antimicrobials, except colistin, and therefore the patients with A. baumannii pneumonia were more likely to receive inappropriate antimicrobial therapy. The 14-day mortality was significantly higher in patients with A. baumannii pneumonia (34.7% vs. 15.3%, p 0.001). A. baumannii was an independent risk factor for mortality (OR, 2.03; 95% CI, 1.05 3.90; p 0.035) in the overall cohort after adjustment for other risk factors for death, including inappropriate antimicrobial therapy. The results demonstrated the difference in clinical presentation, microbial characteristics and outcomes between A. baumannii and A. nosocomialis nosocomial pneumonia, and supported that they are two distinct clinical entities. Keywords: Acinetobacter baumannii, Acinetobacter nosocomialis, antimicrobial therapy, mortality, pneumonia Original Submission: 4 May 2012; Revised Submission: 2 July 2012; Accepted: 8 July 2012 Editor: M. Paul Article published online: 12 July 2012 Clin Microbiol Infect 2013; 19: 640 645 10.1111/j.1469-0691.2012.03988.x Corresponding author: T.-L. Chen, Division of Infectious Diseases, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei, 11217, Taiwan E-mail: tecklayyy@yahoo.com.tw Introduction The phenotypically indistinguishable Acinetobacter baumannii, Acinetobacter nosocomialis (formerly Acinetobacter genomic species 13TU) and Acinetobacter pittii (formerly Acinetobacter genomic species 3) are grouped as the A. baumannii (Ab) group [1,2] and have emerged as leading pathogens of nosocomial pneumonia in critically ill patients [3,4]. To date, there is controversy over whether Ab group pneumonia results in higher mortality [5 7] or inappropriate antimicrobial therapy affects the mortality of patients with Ab group pneumonia [8,9]. The pneumonia caused by phenotypically identified A. baumannii described in many studies actually comprises pneumonia caused by either one of the Acinetobacter species in the Ab group [8,10]. Recently, several studies reported that there are differences in antimicrobial resistance and outcome between A. baumannii and other Acinetobacter species in the Ab group [11 13]. It is unclear whether pneumonia caused by these different Acinetobacter species can be considered as a single clinical entity, or they are different in clinical presentation, microbial characteristics and outcomes. Acinetobacter baumannii and A. nosocomialis are the two most commonly isolated Acinetobacter species in clinical settings [14] and account for more than 80% of infections caused by the Ab group [11,12,15,16]. In this study, the clinical Clinical Microbiology and Infection ª2012 European Society of Clinical Microbiology and Infectious Diseases

CMI Lee et al. Pneumonia caused by Ab group 641 characteristics, microbiological findings and final outcomes of a large number of patients with bacteraemic nosocomial pneumonia caused by A. baumannii and A. nosocomialis were analysed to determine whether nosocomial pneumonia caused by these two Acinetobacter species is a single or distinct clinical entity. Materials and Methods Study population The study was conducted at Taipei Veterans General Hospital (T-VGH) during an 8-year period from July 2000 to August 2008. T-VGH is a 2900-bed tertiary-care teaching hospital located in Taipei, Taiwan. Charts were reviewed for all patients with at least one positive blood culture for A. baumannii or A. nosocomialis who had symptoms and signs of infection. Only the first blood culture from patients with two or more positive blood cultures was included. The criteria for inclusion [17] in this study were (i) at least one positive respiratory sample (sputum, bronchoalveolar lavage or pleural effusion) for the Ab group obtained within 48 h before or after the first positive blood culture; (ii) a clinical course compatible with the diagnosis of pneumonia, including a new pulmonary infiltrate plus one additional criterion (fever 38 C, blood leukocytosis 10 000 cells/mm 3 or leucopenia 3000 cells/mm 3 ), together with one or more of the following conditions: new cough, change of color of sputum, chest pain, and dyspnoea; and (iii) that the positive blood culture was not related to another source of infection. Patients <18 years of age and those with incomplete medical records were excluded. The protocol was approved by the T-VGH Institutional Review Board with a waiver of informed consent. Microbiological studies The presumptive identification of the isolates to the level of the Ab group was performed with the API ID 32 GN system (biomérieux, Marcy l Etoile, France) or Vitek 2 system (bio- Mérieux). A multiplex-pcr method was used to identify A. baumannii to the genomic species level [18]. Isolates identified as non- A. baumannii species of Acinetobacter were identified to the genomic species level by 16S 23S ribosomal DNA intergenic spacer sequence analysis [19]. Antimicrobial susceptibilities were determined by the agar dilution method according to the Clinical Laboratory Standards Institute (CLSI) [20]. Multidrug resistance was defined as resistance to three or more of the following classes of antimicrobial agents: antipseudomonal cephalosporins, antipseudomonal carbapenems, ampicillin/sulbactam, fluoroquinolones and aminoglycosides [1]. Data collection Medical records were reviewed to extract clinical information, including demographic characteristics, underlying diseases, Charlson [21] co-morbidity score, duration of stay in an intensive care unit (ICU), length of hospital stay, time of receipt, dose and route of administration of individual antimicrobials, the mechanical ventilation, central venous catheters, a nasogastric tube, or a foley catheter at the time of onset of bacteremi A. Community-acquired pneumonia (CAP), healthcare-associated pneumonia (HCAP), nosocomial pneumonia and ventilator-associated pneumonia (VAP) were defined according to the 2005 American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines [22]. Chronic lung diseases other than chronic obstructive pulmonary disease (COPD) included asthma, bronchiectasis, pulmonary fibrosis and old pulmonary tuberculosis [23]. Immunosuppressive therapy was defined as receipt of cytotoxic agents within 6 weeks, or corticosteroids at a dosage equivalent to or higher than 10 mg of prednisolone daily for more than 5 days within 4 weeks prior to the onset of bacteremi A. Neutropenia was defined as an absolute neutrophil count <500 per mm 3. Recent surgery was defined as operations performed within 4 weeks prior to the onset of bacteremi A. Chronic kidney disease was defined as an estimated glomerular filtration rate (egfr) <60 ml/min/1.73 m 2. Polymicrobial bacteraemia was defined as isolation of one or more microorganisms other than A. baumannii or A. nosocomialis from blood during the same bacteraemic episode. The illness severity was evaluated using the Acute Physiology and Chronic Health Evaluation II (APACHE II) score [24] within 24 h prior to bacteraemia onset. Appropriate antimicrobial therapy was defined as administration of at least one antimicrobial agent, to which the causative pathogen was susceptible, within 48 h after the onset of bacteraemia, with an approved route and dosage for endorgan(s) function. Antimicrobial therapy that did not meet this definition was considered as inappropriate. Monotherapy with an aminoglycoside was not considered as an appropriate therapy. The primary outcome measure was all-cause 14-day mortality following the onset of A. baumannii or A. nosocomialis bacteraemia, respectively. Statistical analysis To assess differences, the chi-square test with Yate s correction or Fisher s exact test was used to compare the discrete variables; the Student s t-test or Mann Whitney rank sum test was used to analyse continuous variables. Logistic regression models were used to explore independent risk factors for 14-day mortality. Univariate analyses were per-

642 Clinical Microbiology and Infection, Volume 19 Number 7, July 2013 CMI formed separately for each of the risk factor variables to ascertain the odds ratio (OR) and 95% confidence interval (CI). All biologically plausible variables with a p value of 0.20 in the univariate analysis were considered for inclusion in the logistic regression model for the multivariate analysis. A backward selection process was utilized. Time to mortality was analysed using Kaplan Meier survival analysis. A p value <0.05 was considered statistically significant. All the analyses were processed with the Statistical Package for the Social Sciences (SPSS) software version 18.0 (SPSS, Chicago, IL, USA). Results During the study period 770 patients were found to have had at least one episode of bacteraemia caused by the Ab group. Following genomic species analysis, 353 (45.8%) and 333 (43.2%) patients were identified as having had bacteraemia caused by A. baumannii and A. nosocomialis, respectively. We excluded 129 patients with polymicrobial bacteraemia and 288 patients with a positive blood culture attributable to another source of infection. Eight patients with community- Demographic or characteristic A. baumannii (n = 121) A. nosocomialis (n = 131) p value Age, in years 74.0 (58 80) 77 (65 83) 0.05 Gender, male 93 (76.9) 101 (77.1) >0.99 Acquired in ICU 86 (71.1) 92 (70.2) 0.99 Ventilator-associated pneumonia 85 (70.2) 93 (71.0) >0.99 Days of hospitalization prior to culture 23 (11 40) 17 (11 31) 0.14 Co-morbidity Charlson co-morbidity score 3 (2 5) 3 (2 5) 0.77 Hypertension 57 (47.1) 79 (60.3) 0.05 Coronary artery disease 22 (18.2) 24 (18.3) >0.99 Congestive heart failure 21 (17.4) 22 (16.5) >0.99 Cerebral vascular disease 27 (22.3) 34 (26.0) 0.60 COPD 28 (23.1) 40 (30.5) 0.24 Other chronic lung disease 18 (14.9) 14 (10.7) 0.42 Alcoholism 15 (12.4) 7 (5.3) 0.08 Liver cirrhosis 8 (6.6) 10 (7.6) 0.94 Chronic kidney disease 38 (31.4) 37 (28.2) 0.68 Type 2 diabetes mellitus 40 (33.1) 47 (35.9) 0.74 Collagen vascular disease 10 (8.3) 2 (1.5) 0.03 TABLE 1. Demographic and clinical characteristics of patients with bacteraemic nosocomial pneumonia caused by Acinetobacter baumannii and Acinetobacter nosocomialis Usage of immunosupressants Cytotoxic chemotherapy 19 (15.7) 13 (9.9) 0.24 Corticosteroids 24 (19.8) 13 (9.9) 0.04 Malignancy 41 (33.9) 39 (29.8) 0.57 Recent surgery 38 (31.4) 52 (39.7) 0.22 Trauma 4 (3.3) 11 (8.4) 0.15 Procedure a Central venous catheter 80 (66.1) 83 (63.4) 0.75 Foley catheter 89 (73.6) 93 (71.0) 0.75 Haemodialysis 14 (11.6) 13 (9.9) 0.83 Nasogastric tube 111 (91.7) 100 (76.3) 0.002 Thoracic drain 7 (5.8) 12 (9.2) 0.44 Endotracheal tube or tracheostomy 103 (85.1) 103 (78.6) 0.24 Mechanical ventilation 90 (74.4) 94 (71.8) 0.74 Shock a 77 (63.6) 62 (47.3) 0.01 Laboratory parameters a WBC count <4000/mm 3, >12 000/mm 3, or >10% bands 96 (70.6) 75 (56.4) 0.02 Haemoglobin, g/dl 9.2 (8.3 10.5) 10.1 (9.0 11.2) <0.001 Platelet count, 10 3 cells/mm 3 136 (54.8 222) 170 (96 255) 0.04 APACHE II score a 26 (21 34) 24 (18 30) 0.009 Radiological features Lobar consolidation 13 (10.7) 4 (3.1) 0.03 Bilateral radiological involvement 89 (73.6) 93 (71.0) 0.75 Pleural effusion 40 (33.1) 46 (35.1) 0.83 Appropriate antimicrobial therapy 32 (26.4) 69 (52.7) <0.001 Outcome 14-day mortality 42 (34.7) 20 (15.3) 0.001 In-hospital mortality 79 (65.3) 53 (40.5) <0.001 Time to death, days 9 (1 32) 27 (8.5 60.5) 0.003 Data are median value (interquartile range) for continuous variables and number of cases (%) for categorical variables. ICU, intensive care units; COPD, chronic obstructive pulmonary disease; APACHE, Acute Physiology and Chronic Health Evaluation; WBC, white blood cell. a At the time the blood culture was obtained.

CMI Lee et al. Pneumonia caused by Ab group 643 acquired A. baumannii pneumonia, which is a distinct clinical entity, were excluded [23,25]. We also excluded nine patients with HCAP (seven caused by A. baumannii and two by A. nosocomialis). The final population that met the criteria for entry into the study consisted of 121 patients with A. baumannii and 131 patients with A. nosocomialis nosocomial pneumonia. The demographic and clinical characteristics of the study patients are summarized in Table 1. Patients with A. baumannii had more collagen vascular diseases, and more frequently received corticosteroids and had nasogastric tubes than those with A. nosocomialis. The Charlson co-morbidity scores on admission were similar for the two Acinetobacter species. However, patients with A. baumannii had significantly higher APACHE II scores (p 0.003) and more frequently presented with shock at the time positive blood cultures were obtained. Patients with A. baumannii had lower haemoglobin levels and platelet counts, and more frequently presented with leukocytosis or leucopenia, but they did not have more haematological malignancy (data not shown). Pulmonary lobar consolidation was significantly more frequent in patients with A. baumannii pneumonia (p 0.03), while pleural effusion and bilateral lung involvement were about the same with both Acinetobacter species. The antimicrobial susceptibility profiles of the clinical isolates of A. baumannii and A. nosocomialis are shown in Table 2. A. baumannii exhibited significantly higher rates of resistance to all antimicrobials tested, with the exception of colistin. None of the A. baumannii isolates were resistant to colistin. In contrast, 26.7% of the A. nosocomialis isolates were resistant to colistin (p <0.001). Patients with bacteraemic pneumonia caused by A. baumannii were accordingly more likely to receive inappropriate antimicrobial therapy. The 14-day mortality was significantly higher for patients with bacteraemic pneumonia caused by A. baumannii than for A. nosocomialis (34.7% vs. 15.3%, p 0.001). The median time TABLE 2. Comparison of antimicrobial susceptibilities of Acinetobacter baumannii and Acinetobacter nosocomialis isolates Antimicrobial agent Resistance, n (%) A. baumannii (n = 121) A. nosocomialis (n = 131) p value Amikacin 108 (89.3) 53 (40.5) <0.001 Gentamicin 110 (90.9) 84 (64.1) <0.001 Ceftazidime 110 (90.9) 39 (29.8) <0.001 Cefepime 82 (67.8) 31 (23.7) <0.001 Ampicillin/sulbactam 68 (56.2) 40 (30.5) <0.001 Ciprofloxacin 111 (91.7) 15 (11.5) <0.001 Imipenem 49 (40.5) 28 (21.4) 0.002 Tigecycline 18 (14.9) 7 (5.3) 0.02 Colistin 0 (0) 35 (26.7) <0.001 Multidrug resistance 112 (92.6) 63 (48.1) <0.001 to death was significantly shorter for A. baumannii (9 days; interquartile range, 1 32 days) than A. nosocomialis pneumonia (27 days; interquartile range, 8.5 60.5 days) (p 0.003). Kaplan Meier survival curves reflected the early occurrence of death within a few days following pneumonia for patients with A. baumannii. This was followed by slightly higher rates of death for A. baumannii than A. nosocomialis species thereafter (p <0.001, by log-rank test) (Fig. 1). In order to clarify the influence of different Acinetobacter species on 14-day mortality, multivariate logistic regression analysis was performed for the overall cohort to identify independent risk and protective factors for mortality (Table 3). Notably, A. baumannii was an independent risk factor for mortality (OR, 2.03; 95% CI, 1.05 3.90; p 0.035). Discussion This study clearly demonstrates significant differences in the clinical features, microbial characteristics and outcome of bacteraemic nosocomial pneumonia caused by A. baumannii and A. nosocomialis. Compared with patients with A. nosocomialis pneumonia, patients with A. baumannii pneumonia have more collagen vascular disease and use of corticosteroids. Patients with A. baumannii were significantly more likely to have more severe illness as determined by APACHE II score, greater frequency of shock, abnormal haematological findings, lobar pneumonia, antimicrobial resistance, inappropriate use of antimicrobials, shorter time to death and higher mortality. These findings support the concept that bacteraemic pneumonias caused by A. baumannii and A. nosocomialis should be considered as two distinct clinical entities. The shorter time to death and higher mortality of patients infected with A. baumannii compared with A. nosocomialis may be attributed to an unfavourable underlying disease of the Survival probability 1.0 0.8 0.6 0.4 0.2 0.0 0 Survival functions 5 10 Days of follow-up A. nosocomialis A. baumannii FIG. 1. Kaplan Meier survival curves for patients with Acinetobacter baumannii and Acinetobacter nosocomialis bacteraemic nosocomial pneumonia. 15

644 Clinical Microbiology and Infection, Volume 19 Number 7, July 2013 CMI Demographic or characteristic Univariate analysis Odds ratio (95% CI) p Multivariable analysis Odds ratio (95% CI) p Acinetobacter baumannii 2.95 (1.61 5.41) <0.001 2.03 (1.05 3.90) 0.035 Bilateral radiological involvement 1.83 (0.91 3.69) 0.091 2.39 (1.11 5.14) 0.026 Chronic lung diseases other than COPD 1.74 (0.79 3.84) 0.173 Usage of cytotoxic chemotherapy 1.74 (0.79 3.84) 0.173 Usage of corticosteroids 3.40 (1.64 7.07) 0.001 3.58 (1.60 7.98) 0.002 Presence of central venous catheter 1.62 (0.86 3.03) 0.136 Presence of nasogastric tube 2.11 (0.84 5.28) 0.112 Malignancy 1.66 (0.91 3.01) 0.096 2.25 (1.15 4.40) 0.018 Inappropriate antibiotics 3.68 (1.84 7.35) <0.001 3.77 (1.77 8.04) 0.001 TABLE 3. Logistic regression analysis of predictors for 14-day mortality among patients with Acinetobacter baumannii and Acinetobacter nosocomialis bacteraemic nosocomial pneumonia CI, confidence interval; COPD, chronic obstructive pulmonary disease. patients, higher frequency of inappropriate antimicrobial therapy in the former group and possibly higher pathogenicity of A. baumannii [11,12]. Our study showed that although the chronic co-morbidity scores of patients at admission were similar between the two groups, pneumonia caused by A. baumannii was more severe than that caused by A. nosocomialis at the onset of bacteremi A. In addition, A. baumannii is an independent risk factor for mortality after adjustment for other risk factors for death, including inappropriate antimicrobial therapy. The result once again indicated a higher pathogenicity of A. baumannii. Based on the results one could assume that previous papers reporting a negligible attributable mortality of the Ab group [10] might include a large proportion of patients with infections due to A. nosocomialis, while papers reporting a considerable attributable mortality [6] might include mostly patients with real A. baumannii infections. Our findings that higher resistance rates of all antimicrobials except colistin were observed in A. baumannii isolates than in A. nosocomialis [11,15,26] were responsible for the increasing chance of receiving an inappropriate antimicrobial therapy in patients infected with A. baumannii. This might also contribute to the higher mortality in A. baumannii, especially in those with higher APACHE II scores [27]. In conclusion, we recommend that nosocomial pneumonia caused by A. baumannii and A. nosocomialis should be considered as two different clinical entities. Acknowledgements The authors wish to express their appreciation to Calvin M. Kunin for his critical review of the manuscript. Transparency Declaration This study was supported by grants from the Taipei Veterans General Hospital (V101E4-003 and V101C-021), the National Science Council (NSC98-2314-B-010-010-MY3) and the Yen Tjing Ling Medical Foundation (CI-100-35). The authors declare that they have no conflicts of interest. References 1. Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: emergence of a successful pathogen. Clin Microbiol Rev 2008; 21: 538 582. 2. Espinal P, Seifert H, Dijkshoorn L, Vila J, Roca I. Rapid and accurate identification of genomic species from the Acinetobacter baumannii (Ab) group by MALDI-TOF MS. Clin Microbiol Infect 2011; Oct 13; [Epub ahead of print]. doi: 10.1111/j.1469-0691.2011.03696.x. 3. Joly-Guillou ML. Clinical impact and pathogenicity of Acinetobacter. Clin Microbiol Infect 2005; 11: 868 873. 4. Falagas ME, Karveli EA. 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