Departments of 1Medical Microbiology & Immunology and 2Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt *Corresponding Author’s e-mail: amira110sultan@yahoo.com حتديد عوامل اخلطورة لالصابة بالعدوى املرتبطة بالرعاية الصحية اليت تسببها بكترييا أسينيتوباكرت بوماين املقاومة للكاربابنيم يف وحدة العناية املركزة حلديثي الوالدة اأمرية حممد �سلطان و وائل �سليم abstract: Objectives: Acinetobacter baumannii is a causative pathogen of various healthcare-associated infec- tions (HAIs) and is particularly prevalent in high-risk hospital settings. This study aimed to determine risk factors associated with HAIs caused by carbapenem-resistant A. baumannii (CRAB) in a neonatal intensive care unit (NICU). Methods: This prospective study was performed between January 2013 and June 2014 among NICU patients at the Mansoura University Children’s Hospital, Mansoura, Egypt. Neonates who developed HAIs due to CRAB were assigned to a case group, while those infected with carbapenem-sensitive A. baumannii (CSAB) were assigned to a control group. Results: Among the 124 neonates who developed A. baumannii-caused HAIs during the study period, 91 (73.4%) were caused by CRAB and 33 (26.6%) were caused by CSAB. Prematurity, premature rupture of the membranes (PROM), a previous stay in another hospital, prolonged NICU stay, the presence of invasive devices, previous exposure to carbapenems or aminoglycosides and prolonged antibiotic therapy before infection were significantly associated with CRAB-caused HAIs. A multivariate logistic regression analysis identified prematurity (adjusted odds ratio [aOR] = 25.3; P <0.01), mechanical ventilation (aOR = 18.9; P <0.01) and the previous use of carbapenems (aOR = 124.7; P <0.01) or aminoglycosides (aOR = 22.6; P = 0.04) to be independent risk factors for CRAB infections. Conclusion: Various risk factors were significantly associated with CRAB-caused HAIs among the studied NICU patients. Keywords: Healthcare Associated Infections; Antimicrobial Drug Resistance; Carbapenem Antibiotics; Acineto- bacter baumannii; Neonatal Intensive Care Units; Egypt. امللخ�ص: الهدف: تعترب بكترييا اأ�سينيتوباكرت بوماين اأحد م�سببات العدوى املرتبطة بالرعاية ال�سحية. و حيث اأنها تتواجد ب�سكل خا�ض يف مناطق الرعاية ال�سحية ذات اخلطورة العالية فقد هدفت هذه الدرا�سة اىل حتديد عوامل اخلطورة لال�سابة بالعدوى املرتبطة بالرعاية ال�سحية التي ت�سببها بكترييا اأ�سينيتوباكرت بوماين املقاومة للكاربابنيم يف وحدة العناية املركزة حلديثي الوالدة. الطريقة: اأجريت هذه املن�سورة، اجلامعى، االأطفال مب�ست�سفى الوالدة حلديثي املركزة العناية وحدة يف 2014 ويونيو 2013 يناير بني اال�ستطالعية الدرا�سة م�رص. مت ادراج املر�سى امل�سابني بالعدوى املرتبطة بالرعاية ال�سحية الناجتة عن بكترييا اأ�سينيتوباكرت بوماين املقاومة للكاربابنيم يف جمموعة الدرا�سة يف حني مت ادراج املر�سى امل�سابني بالعدوى املرتبطة بالرعاية ال�سحية الناجتة عن بكترييا اأ�سينيتوباكرت بوماين عن الناجتة ال�سحية بالرعاية املرتبطة بالعدوى م�سابا مري�سا 124 ر�سد مت النتائج: ال�سابطة. املجموعة يف للكاربابنيم احل�سا�سة عن الناجتة ال�سحية بالرعاية املرتبطة بالعدوى امل�سابني املر�سى عدد كان قد و الدرا�سة. فرتة خالل بوماين اأ�سينيتوباكرت بكترييا املرتبطة بالعدوى امل�سابني املر�سى عدد كان بينما )73.4%( مري�سا 91 هو للكاربابنيم املقاومة بوماين اأ�سينيتوباكرت بكترييا اخلطورة عوامل �سملت وقد .)26.6%( مري�سا 33 هو للكاربابنيم احل�سا�سة بوماين اأ�سينيتوباكرت بكترييا عن الناجتة ال�سحية بالرعاية اخلدج، االأطفال من كل للكاربابنيم املقاومة بوماين بكترييا اأ�سينيتوباكرت ت�سببها التي ال�سحية بالرعاية املرتبطة بالعدوى لال�سابة والتمزق املبكر لالأغ�سية املحيطة باجلنني، واالقامة يف م�ست�سفى اآخر، واالإقامة لفرتات طويلة يف وحدة العناية املركزة حلديثي الوالدة، اال�سابة قبل طويلة لفرتات احليوية بامل�سادات والعالج اأمينوغليكوزيد�ض اأو للكاربابنيم ال�سابق والتعر�ض اجتياحية، اأجهزة ووجود ،)P >0.01 25.3؛ = )aOR( بالعدوى. وقد بني االنحدار اللوج�ستي متعدد املتغريات اأن كل من االأطفال اخلدج )ن�سبة االأرجحية املعدلة املعدلة االأرجحية )ن�سبة للكاربابنيم ال�سابق واال�ستخدام )P >0.01 18.9؛ = )aOR( املعدلة االأرجحية ))ن�سبة امليكانيكية والتهوية م�ستقلة خطورة عوامل ميثلون )P = 0.04 22.6؛ = )aOR( املعدلة االأرجحية )ن�سبة اأمينوغليكوزيدز اأو )P >0.01 124.7؛ = )aOR( لالإ�سابة بالعدوى املرتبطة بالرعاية ال�سحية التي ت�سببها بكترييا اأ�سينيتوباكرت بوماين املقاومة للكاربابنيم. اخلال�صة: لقد تبني اأنه املقاومة بوماين اأ�سينيتوباكرت بكترييا ت�سببها التي ال�سحية بالرعاية املتعلقة بالعدوى باالإ�سابة مرتبطة خطورة عوامل عدة يوجد للكاربابنيم يف وحدة العناية املركزة حلديثي الوالدة. الكلمات املفتاحية: العدوى املرتبطة بالرعاية ال�سحية؛ امليكروبات املقاومة للم�سادات احليوية؛ م�سادات الكاربابنيم؛ بكترييا اأ�سينيتوباكرت بوماين؛ وحدة العناية املركزة حلديثي الوالدة؛ م�رص. Identifying Risk Factors for Healthcare-Associated Infections Caused by Carbapenem-Resistant Acinetobacter baumannii in a Neonatal Intensive Care Unit *Amira M. Sultan1 and Wael A. Seliem2 clinical & basic research Sultan Qaboos University Med J, February 2018, Vol. 18, Iss. 1, pp. e75–80, Epub. 4 Apr 18 Submitted 23 Oct 17 Revision Req. 20 Dec 17; Revision Recd. 24 Dec 17 Accepted 11 Jan 18 doi: 10.18295/squmj.2018.18.01.012 Identifying Risk Factors for Healthcare-Associated Infections Caused by Carbapenem-Resistant Acinetobacter baumannii in a Neonatal Intensive Care Unit e76 | SQU Medical Journal, February 2018, Volume 18, Issue 1 Healthcare-associated infections (hais) are infections contracted in various health-care settings and are well known to increase morbidity, mortality, length of hospital stay and the cost of medical care.1 Intensive care units (ICUs), including neonatal ICUs (NICUs), constitute high-risk areas for HAIs as admitted patients are usually critically ill and commonly undergo invasive procedures.2 Acine- tobacter baumannii is a major causative pathogen of various HAIs, such as bloodstream infections and pneumonia, particularly in high-risk settings such as ICUs. Unfortunately, recent studies have reported a steady increase in the prevalence of carbapenem- resistant A. baumannii (CRAB) strains isolated from patients with HAIs.3–5 This study therefore aimed to determine risk factors for the development of CRAB- caused HAIs among patients in a NICU in Egypt. Methods This prospective single-centre study was conducted between January 2013 and June 2014 in the NICU of the Mansoura University Children’s Hospital, Man- soura, Egypt. All patients who developed A. baumannii- caused HAIs of any type following their admission to the NICU were included in the study. The identi- fication of A. baumannii strains was performed using colony morphology, microscopic examination and biochemical tests. The API® 20 NE identification system (bioMérieux Inc, St. Louis, Missouri, USA) was used to confirm the diagnosis of an A. baumannii- caused infection. Patients who developed HAIs with A. baumannii isolates showing resistance to imipenem or meropenem were assigned to a case group while those with isolates sensitive to imipenem and meropenem were assigned to a control group. The sensitivity patterns of the isolated A. baumannii strains were detected using the disc diffusion method. All results were interpreted using the guidelines of the Clinical and Laboratory Standards Institute.6 Surveillance procedures conducted for patients with different types of HAIs were performed acc- ording to the definitions, elements and criteria of the Centers for Disease Control and Prevention.7 Infections developing during the first two calendar days of hosp- ital stay were deemed to have been present upon admission, while infections developing on or after the third calendar day of hospital stay were considered HAIs. Information regarding the HAI was collected by reviewing the patients’ medical records and their clinical and laboratory findings. Possible risk factors were documented for each patient, including pre- maturity (<37 gestational weeks); low birth weight (<2,500 g); premature rupture of the membranes; age; gender; previous stay in another hospital; length of NICU stay prior to infection; the presence of an inv- asive device; duration of antibiotic therapy before the HAI; and previous antibiotic exposure. The latter risk factor was considered present only in cases wherein systemic antibiotics were administered for a minimum of 24 hours within the 14-day period prior to the isolation of the A. baumannii strain. In terms of patient outcome, HAI-related mortality was defined as death within 30 days of developing the infection. Statistical analysis was performed using the Stat- istical Package for the Social Sciences (SPSS), Version 22.0 (IBM Corp, Armonk, New York, USA). Nonpara- metric demographic and clinical parameters were com- pared using the Mann-Whitney U test and presented as medians and ranges. Categorical variables were compared using the Chi-squared test and presented as percentages. A multivariate analysis was performed using binary logistic regression to assess independent risk factors for CRAB-caused HAIs. Differences were considered statistically significant at P ≤0.05. Advances in Knowledge - The current study identified significant risk factors associated with healthcare-associated infections (HAIs) caused by carbapenem- resistant Acinetobacter baumannii (CRAB) among patients in a neonatal intensive care unit (NICU) in Egypt. - Significant risk factors included prematurity, premature rupture of the membranes, a previous stay in another hospital, prolonged NICU stay, the presence of an invasive device (i.e. an umbilical catheter, urinary catheter or mechanical ventilator), previous exposure to carbapenems or aminoglycosides and prolonged antibiotic therapy prior to the infection. Application to Patient Care - The findings of this study may be utilised by NICU staff to decrease risk factors associated with carbapenem resistance among Egyptian neonates. Table 1: Healthcare-associated infections caused by carb- apenem-resistant or -sensitive Acinetobacter baumannii in a neonatal intensive care unit in Egypt (N = 124) Type of infection n (%) CRAB (n = 91) CSAB (n = 33) Blood stream 65 (71.4) 22 (66.7) Pneumonia 17 (18.7) 7 (21.2) Urinary tract 7 (7.7) 3 (9.1) Other 2 (2.2) 1 (3) CRAB = carbapenem-resistant Acinetobacter baumannii; CSAB = carbapenem-sensitive A. baumannii. Amira M. Sultan and Wael A. Seliem Clinical and Basic Research | e77 This study received ethical approval from the Institutional Review Board of the Faculty of Medicine, Mansoura University (#R/17.10.10). Informed consent was obtained from a parent or guardian of all of the patients included in the study. Results During the study period, 124 neonates in the NICU developed HAIs caused by A. baumannii. Of these, 91 infections (73.4%) were caused by CRAB and 33 (26.6%) were caused by carbapenem-sensitive A. baumannii (CSAB). In both groups, bloodstream infections were most common [Table 1]. There was no statistically significant difference between the groups in terms of sites of infection. Prematurity, premature rupture of the membranes, a previous stay in another hospital and prolonged NICU stay prior to infection were iden- tified as significant risk factors for CRAB-caused HAIs (P <0.05 each). Moreover, the presence of an umbilical catheter, urinary catheter or mechanical ventilator, previous exposure to carbapenems or aminoglycosides and prolonged antibiotic therapy were also significant risk factors (P <0.05 each). Prematurity (adjusted odds ratio [aOR] = 25.3; P <0.01), mechanical ventilation (aOR = 18.9; P <0.01) and the previous use of carbapenems (aOR = 124.7; P <0.01) or aminoglycosides (aOR = 22.6; P = 0.04) were independent risk factors for CRAB infections [Table 2]. A total of 70 (76.9%) patients with CRAB infect- ions and eight (24.2%) patients with CSAB infections died; this difference in mortality rate between the two groups was statistically significant (P = 0.01). Signif- icant mortality-related risk factors among patients with Table 2: Risk factors associated with healthcare-associated infections caused by carbapenem-resistant or -sensitive Acinetobacter baumannii in a neonatal intensive care unit in Egypt (N = 124) Risk factor Univariate analysis, n (%) Multivariate analysis CRAB (n = 91) CSAB (n = 33) P value aOR (95% CI) P value Postnatal age in days <7 45 (49.5) 18 (54.5) 0.65 ≥7 46 (50.5) 15 (45.5) 0.35 Male gender 39 (42.9) 16 (48.5) 0.78 Prematurity 54 (59.3) 8 (24.2) 0.03* 25.3 (8.4–784.8) <0.01* LBW 29 (31.9) 10 (30.3) 0.88 PROM 42 (46.2) 5 (15.2) 0.01* PSAH 17 (18.7) 2 (6.1) 0.03* Median length of stay in the NICU prior to HAI (range) 10 (6.4–15.2) 4 (2.6–7.9) 0.04* Presence of an invasive device Umbilical catheter 70 (76.9) 11 (33.3) 0.04* PPCL 10 (11) 5 (15.2) 0.85 Urinary catheter 66 (72.5) 7 (21.2) <0.01* MV 72 (79.1) 9 (27.3) <0.01* 18.9 (3.5–1,135.1) <0.01* Previous antibiotic exposure Carbapenems 55 (60.4) 5 (15.2) <0.01* 124.7 (45.2–588.1) <0.01* Cephalosporins 24 (26.4) 6 (18.2) 0.07 Aminoglycosides 42 (46.2) 4 (12.1) 0.02* 22.6 (1.1–864.9) 0.04* Vancomycin 30 (33) 12 (36.4) 0.79 Median duration of antibiotic therapy before HAI in days (range) 8 (5.7–10.4) 2 (1.2–4.6) <0.05* CRAB = carbapenem-resistant Acinetobacter baumannii; CSAB = carbapenem-sensitive A. baumannii; aOR = adjusted odds ratio; CI = confidence interval; LBW = low birth weight; PROM = premature rupture of the membranes; PSAH = previous stay in another hospital; NICU = neonatal intensive care unit; HAI = healthcare-associated infection; PPCL = peripheral percutaneous central line; MV = mechanical ventilator. *Considered statistically significant at P ≤0.05. Identifying Risk Factors for Healthcare-Associated Infections Caused by Carbapenem-Resistant Acinetobacter baumannii in a Neonatal Intensive Care Unit e78 | SQU Medical Journal, February 2018, Volume 18, Issue 1 CRAB infections included prolonged NICU stay, the presence of an umbilical catheter or mechanical vent- ilator and the previous administration of carbapenems (P <0.02 each). Independent risk factors for mortality were mechanical ventilation (aOR = 17.2; P = 0.04) and the previous use of carbapenems (aOR = 79.1; P <0.01) [Table 3]. Isolates from both the CRAB and CSAB groups demonstrated high resistance rates to all anti- microbials except for tigecycline, with no significant differences between the two groups [Table 4]. Discussion The ability to survive in a hospital environment has resulted in a high incidence of HAIs attributed to A. baumannii; furthermore, the organism rapidly deve- lops resistance to a broad range of antibiotic classes.8 Previous research has indicated that the incidence of A. baumannii-resistant strains is increasing all over the world.3–5 According to surveillance data in the USA, carbapenem resistance increased from 5.2% to 40.8% between 1999 and 2010.9 Similarly, in Europe, surv- eillance data from 2012 indicated that 68.8% of A. baumannii strains isolated from ICUs were resistant to carbapenems.10 These findings support those of the present study which indicated a high rate of carba- penem resistance in the studied Egyptian NICU. In terms of invasive procedures, mechanical vent- ilation was the only independent risk factor for CRAB- caused HAIs in the current study. Previous studies have reported similar findings.11,12 Mechanical ventilation is indicated for neonates in cases of respiratory distress, Table 3: Mortality-related risk factors among patients with health-care-associated infections caused by carbapenem- resistant or -sensitive Acinetobacter baumannii in a neonatal intensive care unit in Egypt (N = 124) Variable Univariate analysis, n (%) Multivariate analysis CRAB (n = 70) CSAB (n = 8) P value aOR (95% CI) P value Postnatal age in days <7 32 (45.7) 3 (37.5) 0.38 ≥7 38 (54.3) 5 (62.5) 0.61 Male gender 34 (48.6) 4 (50) 0.80 Prematurity 33 (47.1) 3 (37.5) 0.21 LBW 25 (35.7) 3 (37.5) 0.89 PROM 32 (45.7) 4 (50) 0.42 PSAH 10 (14.3) 1 (12.5) 0.67 Median length of NICU stay prior to HAI (range) 12 (8.3–15.2) 5.4 (3.6–7.9) 0.02* Presence of an invasive device Umbilical catheter 55 (78.6) 1 (12.5) <0.01* PPCL 8 (11.4) 1 (12.5) 0.82 Urinary catheter 54 (77.1) 6 (75) 0.87 MV 57 (81.4) 2 (25) 0.02* 17.2 (2.1–129.2) 0.04* Previous antibiotic exposure Carbapenems 53 (75.7) 1 (12.5) <0.01* 79.1 (32.7–278.9) <0.01* Cephalosporins 18 (25.7) 2 (25) 0.94 Aminoglycosides 20 (28.6) 2 (25) 0.76 Vancomycin 25 (35.7) 3 (37.5) 0.65 Median days of antibiotic therapy before HAI in days (range) 5.1 (3.8–8.7) 3.2 (2.1–3.5) 0.09 CRAB = carbapenem-resistant Acinetobacter baumannii; CSAB = carbapenem-sensitive A. baumannii; aOR = adjusted odds ratio; CI = confidence interval; LBW = low birth weight; PROM = premature rupture of the membranes; PSAH = previous stay in another hospital; NICU = neonatal intensive care unit; HAI = healthcare-associated infection; PPCL = peripheral percutaneous central line; MV = mechanical ventilator. *Considered statistically significant at P ≤0.05. Amira M. Sultan and Wael A. Seliem Clinical and Basic Research | e79 hypoxaemia or hypercapnia; however, organisms present in the hospital environment frequently attach to the ventilator tube and form a biofilm which is associated with an increased risk of antibiotic resistance.13 Further- more, ventilated critically-ill neonates often undergo endotracheal intubation which can interrupt immunity barriers.14 Therefore, the incidence of HAIs may poten- tially be reduced by encouraging the use of noninvasive ventilation among neonates, such as nasal continuous positive pressure ventilation.15 In the current study, a previous stay in another hospital and prolonged NICU stay prior to infection were found to constitute significant risk factors for subsequent CRAB infections. This may be attributable to prolonged exposure to organisms present in the hospital environment and the extended use of anti- biotics that aid in the development of antimicrobial resistance.11,12 Rosa et al. reported that exposure to a contaminated hospital environment increased the risk of acquisition of CRAB isolates.16 Baran et al. indicated that patients admitted to the ICU had a three-fold higher risk of CRAB infections.17 Playford et al. also observed an association between prolonged ICU stay and CRAB infection.18 Unfortunately, the nature of multidrug-resistant microorganisms, including A. bau- mannii, in ICUs is endemic. In addition, the likelihood of antimicrobial therapy increases with the duration of ICU stay, thus leading to the colonisation of resistant strains of bacteria. Previous exposure to carbapenems was another independent risk factor for HAIs caused by CRAB in the present study. Sheng et al. also noted that patients with CRAB infections were significantly more likely to have been exposed to carbapenems.19 Such findings emphasise the need for the judicious use of carba- penem antibiotics, which should remain a last resort in the treatment of serious infections so as to control the development of carbapenem-resistant microbes. As with carbapenems, previous exposure to aminoglyco- sides was another independent risk factor for CRAB infections in the current study. Chen et al. also observed prior exposure to aminoglycosides such as amikacin to be a risk factor for CRAB.20 Treating physicians should therefore consider these findings before prescribing aminoglycosides to ICU patients. In the current study, CRAB isolates showed high resistance rates to other antibiotics. Similar findings were reported by Falagas et al. among pandrug-resistant A. baumannii infection cases.21 Infections caused by multidrug-resistant pathogens have many adverse out- comes, including prolonged hospital stay, higher treat- ment costs and increased mortality rates.22 The treatment of patients suffering from infections caused by such strains is challenging. Adequate knowledge of local A. baumannii resistance patterns is a fundamental element to a successful therapeutic approach.23 In terms of mort- ality, the presence of an umbilical catheter or mechanical ventilator, prolonged stay in the NICU and the previous administration of carbapenems resulted in significantly increased mortality among patients with HAIs caused by CRAB. Similar results were reported by Djordjevic et al. among adult patients admitted to a medical-surgical ICU.24 This study is subject to certain limitations. Generally, NICUs in developing countries such as Egypt usually have low staff-to-patient ratios, often resulting in a lack of essential infection control pre- cautions like thorough hand hygiene and aseptic procedures. Under these conditions, resistant bacteria can more easily spread between patients, resulting in more colonised and infected cases compared to adeq- uately staffed units. In addition, the low number of patients in the control group in comparison to the case group resulted in a wide confidence interval, weak- ening the findings of the present study. Conclusion This study found that prematurity, premature rupture of the membranes, a previous stay in another hosp- ital, prolonged NICU stay, the presence of an invasive device, previous exposure to carbapenems or amino- glycosides and prolonged antibiotic therapy were signif- Table 4: Antimicrobial resistance of carbapenem-resistant and -sensitive Acinetobacter baumannii isolates in a neonatal intensive care unit in Egypt (N = 124) Antimicrobial n (%) P value CRAB (n = 91) CSAB (n = 33) Amoxicillin and clavulanic acid (30 μg/mL) 85 (93.4) 27 (81.8) 0.85 Piperacillin- tazobactam (110 μg/mL) 80 (87.9) 25 (75.8) 0.68 Cefotaxime (30 μg/mL) 91 (100) 33 (100) >0.99 Cefepime (30 μg/mL) 71 (78) 26 (78.8) 0.98 Gentamicin (10 μg/mL) 78 (85.7) 27 (81.8) 0.87 Amikacin (30 μg/mL) 87 (95.6) 29 (87.9) 0.69 Ciprofloxacin (5 μg/mL)* 86 (94.5) 27 (81.8) 0.85 Tigecycline (15 μg/mL) 9 (9.9) 4 (12.1) 0.58 CRAB = carbapenem-resistant Acinetobacter baumannii; CSAB = carb- apenem-sensitive A. baumannii. *Not recommended for use in neonates. Identifying Risk Factors for Healthcare-Associated Infections Caused by Carbapenem-Resistant Acinetobacter baumannii in a Neonatal Intensive Care Unit e80 | SQU Medical Journal, February 2018, Volume 18, Issue 1 icantly associated with CRAB-caused HAIs in an NICU in Egypt. Moreover, prematurity, mechanical ventilation and previous exposure to carbapenems or aminoglyco- sides were independent risk factors for the development of HAIs caused by CRAB. a c k n o w l e d g e m e n t s The authors wish to acknowledge the consistent and helpful support of the nursing staff at the Mansoura University Children’s Hospital in their provision of professional care to the subjects and implementation of proper research protocols during the study period. c o n f l i c t o f i n t e r e s t The authors declare no conflicts of interest. f u n d i n g No funding was received for this study. References 1. Sydnor ER, Perl TM. Hospital epidemiology and infection control in acute-care settings. 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