Multidrug-resistant Acinetobacter baumannii infection among neonates in a neonatal intensive care unit at a medical center in central Taiwan.

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Journal of Microbiology, Immunology and Infection (2014) xx, 1e9

Available online at www.sciencedirect.com

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ORIGINAL ARTICLE

Multidrug-resistant Acinetobacter baumannii infection among neonates in a neonatal intensive care unit at a medical center in central Taiwan Hsiu-Mei Wei a, Yu-Lung Hsu a, Hsiao-Chuan Lin b, Tsung-Hsueh Hsieh a, Ting-Yu Yen a, Hung-Chih Lin c, Bai-Horng Su c, Kao-Pin Hwang b,* a Division of Infectious Diseases, Children’s Hospital, China Medical University and China Medical University Hospital, Taichung, Taiwan b Division of Infectious Diseases, College of Medicine and Department of Pediatrics, Children’s Hospital of China Medical University and China Medical University Hospital, Taichung, Taiwan c Division of Neonatology, College of Medicine and Department of Pediatrics, Children’s Hospital of China Medical University and China Medical University Hospital, Taichung, Taiwan

Received 30 April 2014; received in revised form 29 August 2014; accepted 31 August 2014

Available online - - -

KEYWORDS Acinetobacter baumannii; mortality; multidrug-resistant; neonatal intensive care unit; neonate

Background: Few studies have focused on multidrug-resistant Acinetobacter baumannii (MDRAB) infection in neonates. The aim of this study was to investigate risk factors for mortality in neonates with MDRAB infection. Methods: This retrospective case-series study was conducted at the Children’s Hospital of China Medical University, Taichung, Taiwan. All patients hospitalized between January 2010 and December 2013 in the neonatal intensive care unit (NICU) with MDRAB infections were reviewed. Results: A total of 67 isolates from 59 neonatal patients were positive for MDRAB. Of the 67 isolates, 38 were from blood (56.72%), 16 from sputum (23.88%), seven from pus (10.45%), three from ascites (4.48%), two from cerebrospinal fluid (2.99%), and one from pleural fluid (1.49%). There were five episodes of MDRAB clusters consisting of 28 cases during the study period. The mortality rate due to MDRAB sepsis was 20.34% (12/59). The statistically significant risk factors for mortality due to MDRAB infection were being infected with MDRAB within 7 days of admission to the NICU, use of umbilical vein catheters, absolute neutrophil count < 1500/

* Corresponding author. Pediatric Infectious Diseases, China Medical University Hospital, College of Medicine, China Medical University, Number 2, Yuh-Der Road, Taichung 40447, Taiwan. E-mail addresses: [email protected], [email protected] (K.-P. Hwang). http://dx.doi.org/10.1016/j.jmii.2014.08.025 1684-1182/Copyright ª 2014, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. All rights reserved.

Please cite this article in press as: Wei H-M, et al., Multidrug-resistant Acinetobacter baumannii infection among neonates in a neonatal intensive care unit at a medical center in central Taiwan, Journal of Microbiology, Immunology and Infection (2014), http://dx.doi.org/ 10.1016/j.jmii.2014.08.025

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H.-M. Wei et al. mm3, platelet count < 100,000/mm3, and a delay in initiating adequate antibiotic treatment. Conclusion: MDRAB infection is responsible for a high mortality rate among neonates in the NICU, especially in those who have neutropenia or thrombocytopenia. Infection control and appropriateness of the initial antimicrobial agent with colistin play an important role in reducing mortality. Copyright ª 2014, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. All rights reserved.

Introduction Acinetobacter baumannii is an aerobic, pleomorphic, and nonmotile Gram-negative bacillus and an opportunistic bacterial pathogen primarily associated with hospitalacquired infections.1,2 It causes many clinical infections such as lower respiratory tract infections, urinary tract infections, wound infections, bacteremia, and meningitis. The rapid global emergence of A. baumannii strains resistant to multiple antibiotics has increased the threat to health care systems worldwide. Multidrug-resistant Acinetobacter baumannii (MDRAB) is defined as A. baumannii resistant to three or more than three of the following classes of antimicrobials: aminoglycosides, antipseudomonal carbapenems, antipseudomonal fluoroquinolones, antipseudomonal penicillins plus betalactamase inhibitors, extended-spectrum cephalosporins, folate pathway inhibitors, penicillins þ b-lactamase inhibitors, polymyxins, and tetracycline. Pandrug-resistant A. baumannii is defined as A. baumannii resistant to all of the antimicrobial categories listed above.3 Numerous clinical studies have reported the risk factors for infections from the resistant strains of Acinetobacter species.4e9 However, only a few studies have focused on risk factors for MDRAB infection in neonates.10 Patients with MDRAB infection have a significantly longer duration of intensive care unit (ICU) stay and hospitalization.7 MDRAB infection has also been reported to lead to a higher mortality rate compared with infections of the susceptible type of A. Baumannii.8,10 Despite the high mortality rate associated with MDRAB infections,10e12 few studies have reported on the high mortality rate among neonates.10 Nevertheless, the high mortality rate resulting from MDRAB infection in the neonatal population is also a matter of great concern. Therefore, the aim of this study was to investigate risk factors associated with mortality in neonates with MDRAB infection.

Materials and methods The NICU of the Children’s Hospital of China Medical University is a tertiary-level medical center in central Taiwan with a total of 20 beds. All neonates with at least one episode of MDRAB infection during their hospitalization in the NICU were identified from January 1, 2010 to December 31, 2013. Data including demographic characteristics, perinatal findings, presence of central venous catheters (CVCs), peripheral central venous catheters (PCVCs),

umbilical vein catheters, history of surgery, total parenteral nutrition (TPN) and/or lipid usage, mechanical ventilation including nasal continuous positive airway pressure (NCPAP) and high frequency oscillation (HFO), previous antibiotic exposure duration, adequate prompt antibiotic treatment, and laboratory data were collected and analyzed.

Antimicrobial susceptibility testing A BD Phoenix NMIC/ID-2 commercial kit (Becton Dickinson Diagnostic Systems, Sparkes, MD, USA) was used for antibiotic susceptibility testing. The antibiotics tested included amikacin, ceftazidime, cefpirome, ciprofloxacin, colistin, cefepime, gentamicin, imipenem, levofloxacin, meropenem, ampicillinesulbactam, trimethoprim/sulfamethoxazole, and piperacillin/tazobactam. Susceptibility breakpoints were based on those defined by the Clinical and Laboratory Standards Institute (CLSI) guidelines, 2010.13 The disc diffusion method for tigecycline was used according to the Journal of Clinical Microbiology, 2007 (R 12 mm, I: 13e15 mm, S 16 mm).14

Definitions Premature rupture of the membranes (PROM) in pregnancy refers to rupture of membranes of the amniotic sac and chorion > 18 hours prior to the onset of labor, whereas preterm premature rupture of membranes (PPROM) refers to rupture of the membranes with a gestation of < 37 weeks, > 18 hours prior to the onset of labor. Prolonged hospitalization was defined as an infant who was in the NICU after a postconceptional age of 42 weeks. Recurrent bacteremia was defined as any new episode of documented blood stream infection by the same or different pathogen occurring at least 2 weeks after the initial episode, during which time blood cultures were negative. Bronchopulmonary dysplasia (BPD) was defined according to the consensus conference of the United States National Institute of Child Health and Human Development.15 Intraventricular hemorrhage (IVH) was graded according to a sonographic grading system.16,17 Necrotizing enterocolitis (NEC) was defined according to the modified Bell staging criteria for necrotizing enterocolitis in neonates. Cholestasis was defined according to the definition of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.18,19 Prolonged intubation was defined as the need for endotracheal tube insertion with mechanical ventilation for > 14 days prior to the infection, for which


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Multidrug-resistant Acinetobacter baumannii infection in neonatal patients continuous mandatory ventilation or high frequency oscillation mode was given. Ventilator use was defined as ever having used a ventilator with continuous mandatory ventilation, high frequency oscillation and NCPAP mode. The use of central venous catheters (central lines) was defined as ever having used a PCVC, femoral CVC, or umbilical vein catheter. Death was considered attributable to sepsis if it occurred within 7 days of a positive culture or if clinical signs and symptoms of sepsis were documented in the medical records as the direct cause of death.20 Appropriate prompt antibiotic treatment with colistin was defined as the use of colistin as soon as the culture results proved MDRAB or prior to the culture results.

Statistical analysis All statistical analyses were performed using SPSS software (version 19.00; SPSS Inc., Chicago, IL, USA). A two-sided p < 0.05 was considered to be statistically significant. Univariate Cox proportional hazards models were used to assess the risk factors contributing to mortality among the neonatal patients with MDRAB infection. A multivariate Cox proportional hazards model was used to determine the independent risk factors associated with mortality among the neonates who had MDRAB infection. All variables that were statistically significant in univariate analysis were entered into multivariate analysis to assess their association with mortality.

Results Fifty-nine neonates with MDRAB infection were identified from those hospitalized in the NICU from January 1, 2010 to December 31, 2013. Details of the cases of MDRAB infection and mortality per year are presented as a histogram in Fig. 1. The infants with MDRAB infection had a mean gestational age and birth weight of 29 weeks and 1178 g, respectively. The female-to-male ratio was 0.79:1. All of the patients were receiving ventilator support at the time of infection, and approximately half (34/59, 57.63%) received prolonged intubation. The demographic and clinical characteristics of the patients are summarized in Tables 1 and 2. A total of 67 isolates from the 59 neonatal patients were positive for MDRAB. Of these 67 isolates, 38 were from blood (56.72%), 16 from sputum (23.88%), seven from pus (10.45%), three from ascites (4.48%), two from cerebrospinal fluid (CSF; 2.99%), and one from pleural fluid (1.49%).

Figure 1. The incidence of mortality and number of MDRAB infections per year during the study period (from January 2010 to December 2013). MDRAB Z multidrug-resistant Acinetobacter baumannii.

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There are eight neonates having MDRAB infections on different parts at the same time. Four of them had MDRAB infections detected in isolates from both blood and sputum, one from CSF and sputum, one from blood and pus, one from blood and ascites, and one from ascites and pus. There were no recurrent MDRAB infections in this study. The mortality rate was 20.34% (12/59). Twelve cases died due to MDRAB infection, including 10 from bacteremia, one isolate detected in only the sputum, and one from a pleural fluid infection. Of the 15 isolates from these 12 cases, 10 were from blood, four from sputum, and one from pleural fluid. The mortality rates from the different sites were as follows: blood, 26.31% (10/38); sputum 25% (4/16); and pleural fluid 100% (1/1). Three neonates had both blood and sputum cultures positive for MDRAB infection. The mortality rate from sputum cultures alone was 10% (1/10). The 10 neonates who were culture positive from sputum alone also had pneumonia and sepsis when the sputum culture revealed MDRAB. The two neonates who were CSF culture positive both survived. Five episodes of MDRAB clusters consisting of 28 cases were noted during the study period. The antimicrobial susceptibility patterns of these 28 cases among the five episodes with a total of 30 isolates are shown in Table 3. As the MDRAB clustering was a cause for concern, eight isolates from four neonates and four from the environment in the NICU were simultaneously sent for pulsed-field gel electrophoresis testing as shown in Fig. 2. Tables 1 and 2 show that several risk factors may have been related to mortality in the neonates with MDRAB infections. These risk factors included a stay in the NICU for < 7 days (p < 0.01), no prolonged hospitalization (p Z 0.012), being infected with MDRAB within 7 days of admission to the NICU (p Z 0.033), no surgical history (p Z 0.01), no BPD (p Z 0.006), no recurrent sepsis (p Z 0.028), no appropriate prompt antibiotic treatment with colistin (p Z 0.024), no prolonged intubation (p Z 0.005), shorter ventilator use, shorter NCPAP use (p < 0.001), shorter central line use (p Z 0.002), shorter PCVC use (p Z 0.001), use of femoral CVC for a duration of < 7 days (p Z 0.038), use of umbilical vein catheters (p Z 0.026), shorter TPN and/or Intrafat use (p Z 0.003), absolute neutrophil count < 1500/mm3 (p Z 0.027), and platelet count < 100,000/mm3 (p Z 0.031). Perinatal factors including vaginal delivery, PROM or PPROM, maternal fever, chorioamnionitis, 5-minute Apgar score of 7, perinatal asphyxia and/or hypoxic ischemic encephalopathy were not associated with mortality in the neonates with MDRAB infection. In addition, complications including IVH Grade III, NEC Stage II, recurrent sepsis, and other factors such as previous antibiotics use, leukocytosis, bandemia, and anemia were also not associated with mortality in the infants with MDRAB infection. Multivariate analysis (Table 4) revealed that appropriate prompt antibiotic treatment with colistin significantly decreased the risk of mortality.

Discussion Newborns receiving care in an NICU are at an increased risk of nosocomial infections because of immaturity of the


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H.-M. Wei et al.

Table 1

The demographic characteristics and perinatal findings of the 59 neonatal patients infected with MDRAB Mean (range), n (ratio:%), or n (%)

Characteristics Sex Female Male Gestational age (wk) < 28 2832 > 3237 > 37 Birth body weight (g) 1500 > 1500 Vaginal delivery No Yes PROM/PPROM No Yes Maternal fever No Yes Chorioamnionitis No Yes 5-min APGAR score >7 7 Perinatal asphyxia and/or hypoxic ischemic encephalopathy No Yes NICU stay (d) 7 >7 Prolonged hospitalization No Yes Days of MDRAB infection during NICU stay 7 8e30 > 30 IVH Grade III No Yes NEC Stage II No Yes

Mortality status, N (%) No mortality due to MDRAB sepsis (N Z 47)

pa

HR (95% CI)

p

Death due to MDRAB sepsis (N Z 12)

F/M:0.79

0.890 20 (42.55) 27 (57.45)

6 (50.00) 6 (50.00)

1.000 0.776 (0.250, 2.408)

0.661

1.000 0.677 (0.169, 2.707) 3.221 (0.648, 16.013) 3.069 (0.367, 25.643)

0.581 0.153 0.301

1.000 2.332 (0.702, 7.748)

0.167

1.000 2.785 (0.883, 8.781)

0.080

1.000 0.314 (0.069, 1.433)

0.135

0.178b

29 (23e41) 25 19 2 1

(53.19) (40.43) (4.26) (2.13)

6 3 2 1

(50.00) (25.00) (16.67) (8.33) 0.209b

1178.08 (5084050) 40 (85.11) 7 (14.89)

8 (66.67) 4 (33.33) 0.093b

21 (35.59) 33 (70.21) 14 (29.79)

5 (41.67) 7 (58.33) 0.180b

22 (37.29) 27 (57.45) 20 (42.55)

10 (83.33) 2 (16.67) 0.573b

4 (6.78) 43 (91.49) 4 (8.51)

12 (100.00) 0 (0.00)

40 (85.11) 7 (14.89)

12 (100.00) 0 (0.00)

d d 0.326b

7 (11.86)

d d 0.277b

16 (27.12) 36 (76.60) 11 (23.40)

7 (58.33) 5 (41.67)

1.000 2.143 (0.679, 6.757)

0.193

> 0.99b

1 (1.69)

46 (97.87) 1 (2.13)

12 (100.00) 0 (0.00)

1 (2.13) 46 (97.87)

6 (50.00) 6 (50.00)

< 0.001b,*

74.73 (3e226)

d d 1.000 0.048 (0.014, 0.162)

< 0.001*

0.012b,*

18 (30.51) 29 (61.70) 18 (38.30)

12 (100.00) 0 (0.00)

d d 0.033b,*

13.54 (268) 17 (36.17) 26 (55.32) 4 (8.51)

9 (75.00) 2 (16.67) 1 (8.33)

1.000 0.177 (0.038, 0.819) 0.490 (0.062, 3.871)

0.027* 0.499

1.000 1.866 (0.504, 6.903)

0.350

1.000 0.354 (0.046, 2.740)

0.320

0.409b

10 (16.95) 40 (85.11) 7 (14.89)

9 (75.00) 3 (25.00) 0.432b

11 (18.64) 37 (78.72) 10 (21.28)

11 (91.67) 1 (8.33)


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Multidrug-resistant Acinetobacter baumannii infection in neonatal patients

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Table 1 (continued ) Mean (range), n (ratio:%), or n (%)

Surgical history No Yes Cholestasis No Yes BPD No Yes Recurrent sepsis No Yes



21 (44.68) 26 (55.32)

11 (91.67) 1 (8.33)

27 (45.76)

pa

HR (95% CI)

p

0.010* 1.000 0.090 (0.012, 0.694)

0.021*

1.000 0.261 (0.034, 2.019)

0.198

0.260b

14 (23.73) 34 (72.34) 13 (27.66)

11 (91.67) 1 (8.33) 0.006b,*

19 (32.20) 28 (59.57) 19 (40.43)

12 (100.00) 0 (0.00)

d d 0.028b,*

14 (23.73) 32 (69.57) 14 (30.43)

12 (100.00) 0 (0.00)

d d

a

Chi-square test. Fisher’s exact test. * p < 0.05. BPD Z bronchopulmonary dysplasia; IVH Z intraventricular hemorrhage; NEC Z necrotizing enterocolitis; NICU Z neonatal intensive care unit; PPROM Z preterm premature rupture of membranes; PROM Z premature rupture of the membranes. b

immune system and barrier functions of the skin and gastrointestinal tract, and the invasive diagnostic and therapeutic procedures they undergo.10,21 A. baumannii can be found in up to 25% of normal human skin flora, and dissemination via contaminated hands of hospital personnel during outbreaks has been demonstrated.22,23 In the current study, newborns were enrolled in the NICU from January 2010 to December 2013 with MDRAB infection, and a total of 67 isolates from 59 neonates were found, mostly from sterile sites. These MDRAB isolates were found sporadically before January 2010, but more often thereafter. Therefore, the annual mortality rates during the study period increased. The annual mortality rates in the NICU from 2006 to 2009 were 1.34%, 2.45%, 0.61%, and 1.26%, respectively, increasing to 3.6%, 3.79%, 4.38%, and 2.89% from 2010 to 2013, respectively. There were five episodes of clusters including 28 cases during the study period. The antimicrobial susceptibility patterns of these 28 cases are shown in Table 3, which reveals that almost all of the isolates had the same susceptibility pattern. The pulsed-field gel electrophoresis (PFGE) examination shown in Fig. 2 also reveals a similar pattern except for one of the eight isolates. Of these eight isolates, four were from neonates’ blood and four were from the environment. This implies that MDRAB may have colonized in the NICU, resulting in those five clusters of MDRAB infections. The hospital environment is known to serve as a reservoir for A. baumannii which can survive on desiccated surfaces for prolonged periods of time,24,25 with a reported overall mean survival time of 27 days (range 2133 days).26 Episodes of A. baumannii bacteremia in intensive care units have been reported as clustered epidemics with contamination of environmental sources or hand carriage by health care workers leading to colonization and subsequent infection.2730 Investigations by the infection control team of China Medical University Hospital revealed that high risk areas of MDRAB colonization are the gate surfaces of

incubator windows, the control panel surface of the incubator/ventilator/electrocardiogram (EKG) monitor/airconditioner, the surface of operating tables, taps of suction machines, keyboards, chest percussion devices, beds, and the box for human milk preservation in a refrigerator. The infection control team collected isolates from these high risk areas which also revealed MDRAB colonization, and the antimicrobial susceptibility patterns were almost the same as those only sensitive to colistin and tigecycline. The infection control team reported the results of the susceptibility pattern and the PFGE in March 2013 to all medical staff who worked at the NICU, and emphasized the importance of hand hygiene and adequately disinfecting the environment, and raised awareness of the correct aseptic techniques for invasive procedures. In addition, the infection control team also found that changing certain object storage sites from where they could easily be contaminated was an urgent issue. After these recommendations had been acted on, the episodes of MDRAB infection clusters gradually decreased. The mortality rate due to MDRAB infection in the NICU during the study period was 20.34%. A mortality rate as high as 37.5% was reported in a previous NICU study.10 In Taiwan, a previous study on adult patients with MDRAB infection reported a 30-day mortality rate of 49%,11 and another study at the same hospital on pediatric patients reported a 30-day mortality rate of 42.3%.12 Some of the statistically significant risk factors for mortality in this study were unexpected, such as an NICU stay < 7 days, no prolonged hospitalization, no surgical history, no BPD, no recurrent sepsis, no prolonged intubation, shorter ventilator use, shorter NCPAP use, shorter central line use, shorter PCVC use, and shorter TPN and/or Intrafat use. Most of the patients who died in the current study (9/12 patients; Table 1) had a shorter NICU stay and had been in the NICU for < 7 days when they became infected with MDRAB. The definition of mortality due to


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H.-M. Wei et al. Table 2

The clinical characteristics and laboratory data of the 59 neonatal patients infected with MDRAB Mean (range), n (ratio:%), or n (%)

Antibiotic use Previous antibiotic use (d) 7 >7 Timely colistin use No Yes Invasive procedures Prolonged intubation No Yes Ventilator use (d) 14 > 14 NCPAP use (d) 14 > 14 HFO use (d) No Yes Central line (d) No use 7 >7 PCVC (d) No use 7 >7 Femoral CVC (d) No use 7 >7 Umbilical vein catheter (d) No use 7 TPN and/or Intrafat use (d) No use 7 >7 Laboratory data WBC > 15,000/mm3 No Yes ANC (/mm3) < 1500 1500 Bands (%) < 10 10 Hb (g/dL) < 10 10


pa

HR (95% CI)

p


9.19 (234)

0.608 25 (53.19) 22 (46.81)

8 (66.67) 4 (33.33)

1.000 0.595 (0.179, 1.977)

0.397

1.000 0.264 (0.083, 0.837)

0.024*

1.000 0.052 (0.007, 0.407)

0.005*

1.000 0.021 (0.003, 0.166)

< 0.001*

0.055b 7 (14.89) 40 (85.11)

5 (41.67) 7 (58.33)

14 (29.79) 33 (70.21)

11 (91.67) 1 (8.33)

< 0.001*

34 (57.63)

< 0.001b,*

49.46 (3180) 5 (10.64) 42 (89.36)

11 (91.67) 1 (8.33) < 0.001*

22.69 (1124) 17 (36.17) 30 (63.83)

12 (100.00) 0 (0.00)

36 (76.6) 11 (23.4)

8 (66.67) 4 (33.33)

d d 0.479b

1.93 (221)

1.000 1.432 (0.431, 4.757)

0.558

0.002b,*

25.73 (3140) 2 (4.26) 3 (6.38) 42 (89.36)

0 (0.00) 6 (50.00) 6 (50.00)

4 (8.51) 3 (6.38) 40 (85.11)

5 (41.67) 3 (25.00) 4 (33.33)

44 (93.62) 0 (0.00) 3 (6.38)

10 (83.33) 1 (8.33) 1 (8.33)

d 8.009 (2.549, 25.163) 1.000

< 0.001*

0.001b,*

23.98 (3140)

1.000 0.781 (0.186, 3.278) 0.112 (0.030, 0.422)

0.736 0.001*

1.000 9.520 (1.136, 79.783) 1.333 (0.171, 10.420)

0.038 0.784

1.000 3.990 (1.282, 12.416)

0.017*

1.000 1.877 (0.529, 6.661) 0.178 (0.033, 0.975)

0.330 0.047*

1.000 0.540 (0.118, 2.465)

0.426

1.000 0.230 (0.073, 0.726)

0.012*

1.000 1.698 (0.459, 6.278)

0.428

1.000 1.440 (0.186, 11.155)

0.727

0.223b

1.12 (227)

0.026b,*

0.83 (27) 39 (82.98) 8 (17.02)

6 (50.00) 6 (50.00) 0.003b,*

14.64 (0139) 10 (21.28) 6 (12.77) 31 (65.96)

4 (33.33) 6 (50.00) 2 (16.67) 0.712b

34 (72.34) 13 (27.66)

10 (83.33) 2 (16.67) 0.027b,*

10 (21.28) 37 (78.72)

7 (58.33) 5 (41.67) 0.409b

40 (85.11) 7 (14.89)

9 (75.00) 3 (25.00) > 0.99b

6 (12.77) 41 (87.23)

1 (8.33) 11 (91.67)


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Table 2 (continued ) Mean (range), n (ratio:%), or n (%)

pa

Mortality status, N (%)

Platelets (/mm3) < 100,000 100,000

No mortality due to MDRAB sepsis (N Z 47)


25 (53.19) 22 (46.81)

10 (83.33) 2 (16.67)

HR (95% CI)

p

0.098b 1.000 0.164 (0.032, 0.849)

0.031*

a

Chi-square test. Fisher’s exact test. * p < 0.05. ANC Z absolute neutrophil count; femoral CVC Z femoral central venous catheter; Hb Z hemoglobin; HFO Z high frequency oscillation; NCPAP Z nasal continuous positive airway pressure; PCVC Z peripheral central venous catheter; TPN Z total parenteral nutrition; WBC Z white blood cell count. b

Table 3

The antimicrobial susceptibility patterns of 28 cases among five episodes with a total of 30 isolates

Date

November 2010

November 2011

March 2012

August 2012

January 2013

Source of isolates

Sample

Case Case Case Case Case Case Case Case Case Case Case Case Case Case Case Case Case Case Case Case Case Case Case Case Case Case

1 2 3 4 5 1 2 3 4 5 6 7 1 2 3 4 5 1 2 3 4 4 5 6 1 2

Case Case Case Case

3 4 4 5

Blood Pus Blood Blood Blood Blood Blood Blood Sputum Sputum Sputum Blood Pus Blood Sputum Sputum Blood Blood Blood Sputum Blood Sputum Blood Blood Blood Pleural effusion Pus Blood Sputum CSF

Antimicrobial susceptibility SAM I R R R R R R R R R R R R R R R R R R R R R R R R R R R R R

TGC

LVX

MEM

GM

AN

CAZ

IPM

TZP

CIP

SXT

FEP

CPO

CL

R R R R R R R R R R R R R R R R R R R R R R R R R R


R R R R R R R R R R R R R R R S R R R R R R R R R R







R R R R R R R R R R R

S S S S S S S S S S


S S S S S S S S S S S S S S S S S S S S S S S S S S

S S I I

R R R R

R R R R

R R R R

R R R R

R R R R

R R R R

R R R R

R R R R

R R R R

R R R R

S S S S I S S S S S

S S S S

AN Z amikacin; CAZ Z ceftazidime; CIP Z ciprofloxacin; CL Z colistin; CPO Z Cefpirome; FEP Z cefepime; GM Z gentamicin; IPM Z imipenem; LVX Z levofloxacin; MEM Z meropenem; SAM Z ampicillin-sulbactam; SXT Z trimethoprim/sulfamethoxazole; TGC Z tigecycline; TZP Z piperacillin/tazobactam. Susceptibility breakpoints were based on those defined by the Clinical and Laboratory Standards Institute (CLSI) guidelines, 2010. The disc diffusion method for tigecycline was used according to the Journal of Clinical Microbiology, 2007.


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H.-M. Wei et al. Table 4 Multivariate Cox proportional hazard regression analysis of the 59 neonatal patients’ characteristics contributing to mortality from MDRAB infection Baseline characteristics

Figure 2. The pulsed-field gel electrophoresis results of eight isolates from neonates and the NICU environment in March 2013. Similarities in PFGE pattern were found across all samples except for CMUH-PED-04, suggesting that most neonates shared a common strain of MDRAB as that found in the NICU environment. Source of isolates: CMUH-PED-01, control panel surface of an EKG monitor; CMUH-PED-02, control panel surface of an incubator; CMUH-PED-03, gate surface of an incubator window; CMUH-PED-04, surface of an operating table; and CMUH-PED05w08, neonatal blood culture. CMUH-PED Z China Medical University Hospital-Pediatrics; MDRAB Z multidrug-resistant Acinetobacter baumannii; NICU Z neonatal intensive care unit; PFGE Z pulsed-field gel electrophoresis.

MDRAB infection in this study was death occurring within 7 days of a positive culture result. Thus, these nine neonates died after < 2 weeks hospitalization. As a large proportion of the cases of mortality died early, this may have led to errors in the statistical analysis. All parameters including “duration” may therefore not be reliable, even if it showed statistical significance. For example, complications such as BPD and recurrent sepsis needed > 2 weeks to reach their definition. Invasive procedures including the use of a ventilator, central lines, and TPN and/or Intrafat seemed to be negative risk facts, although this may also be because the patients died early and further studies are needed to clarify this issue. With regards to surgical history, only one of the 12 neonates underwent surgery (Table 1). The unequal distribution of these two groups may mean that this factor is not suitable for statistical analysis. With regards to umbilical vein use, six neonates died and six did not (Table 2). It is possible that the statistical significance in the umbilical vein use group increased the risk of mortality. In a previous study, the authors found that anemia and leukopenia were risk factors for mortality, but not thrombocytopenia.10 In the current study, it was also found that leukopenia and thrombocytopenia were indicators of a poor prognosis. Thirteen out of 59 neonates had both leukopenia and thrombocytopenia, of whom six died of MDRAB infection. In addition, the timely use of colistin in the current study resulted in a lower mortality rate. There were no records of impaired renal function among the studied neonates, even in the colistin group. Due to the clusters of MDRAB infection noted in the NICU during the study period and the high mortality rate associated with MDRAB infection, using colistin as the empirical antibiotic if neonates show signs of sepsis, and especially when neonates in close proximity have MDRAB infection, is recommended.

Sex Female Male NICU stay (d) 7 >7 In which day to get 7th 8th30th > 30th Surgical history No Yes Timely colistin use No Yes PCVC use (d) No use 7 >7 Femoral CVC (d) No use 7 >7 Umbilical vein (d) No use 7 TPN use (d) No use 7 >7 ANC (/mm3) < 1500 1500 Platelets (/mm3) < 100,000 100,000

Mortality HR

95% CI

1.000 0.212

(0.020, 2.208)

1.000 4.512 (0.080, 254.618) MDRAB infection (d) 1.000 0.047 (0.002, 1.122) 0.144 (0.001, 14.952)

p

0.195

0.464

0.059 0.414

1.000 0.133

(0.009, 2.005)

0.145

1.000 0.039

(0.003, 0.51)

0.013*

1.000 0.598 0.345

(0.030, 11.951) (0.010, 11.382)

0.736 0.551

1.000 4.099 1.742

(0.151, 111.246) (0.022, 135.851)

0.402 0.803

1.000 4.868

(0.365, 64.982)

0.231

1.000 2.835 0.206

(0.357, 22.524) (0.005, 8.185)

0.324 0.401

1.000 0.392

(0.062, 2.476)

0.319

1.000 0.120

(0.010, 1.366)

0.087

* p < 0.05. ANC Z absolute neutrophil count; femoral CVC Z femoral central venous catheter; NICU Z neonatal intensive care unit; PCVC Z peripheral central venous catheter; TPN Z total parenteral nutrition.

MDRAB infection is responsible for a high mortality rate among neonates in the NICU, reaching 20.34% in the current study. Neonates with MDRAB infection with neutropenia or thrombocytopenia had a higher mortality rate. Infection control and appropriateness of the initial antimicrobial agent with colistin play an important role in reducing mortality.

Conflicts of interest All authors have no conflicts of interest to declare.


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Acknowledgments The authors thank the nosocomial infection control team at China Medical University Hospital and all medical and nursing staff working in our NICUs for keeping detailed patient records, which contributed greatly to the completion of this research.

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15. 16.

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