1Departments of Microbiology & Immunology, National University of Science and Technology, Sohar, Oman; 2Department of Epidemiology and Public Health, All India Institute of Medical Sciences, Mangalgiri, India; 3Department of Pathology, Sohar Hospital, Sohar, Oman; 4Department of Medical Microbiology and Immunology, Faculty of Medicine, Mansoura University, Egypt *Corresponding Author’s e-mail: mohanbs@nu.edu.om الستينوتروفوموانس مالتوفيليا أحد مسببات األمراض االنتهازية الناشئة يف مستشفيات الرعاية الثالثية يف حمافظة مشال الباطنة، عمان موهان بيليكاالهايل �صاناثيممابا، فينود بي نامبيار، راجيف اأرافينداك�صان، ن�صوى حممد الق�صبي abstract: Objectives: Stenotrophomonas maltophilia, a Gram-negative non-fermentative bacillus, has emerged as an important nosocomial pathogen in recent years. It is intrinsically resistant to many antibiotics and has the ability to acquire antibiotic resistance by multiple mechanisms. Treating Stenotrophomonas infections, therefore, is a serious challenge for physicians. This study aimed to investigate the antibiotic susceptibility patterns and risk factors contributing to S. maltophilia infections. Methods: A retrospective cross-sectional study was conducted at Sohar Hospital in Sohar, Oman. The demographic, clinical and microbiological data of individuals from whom S. maltophilia was isolated between September 2016 and August 2019 were reviewed. Descriptive statistics were presented as frequencies and percentages. Results: A total of 41 S. maltophilia isolates from clinical specimens of 41 patients were studied. Infection occurred predominantly in males (73%) and the majority of patients (88%) were either ≤5 years old or >60 years old. All inpatients had at least one comorbidity while 50% had more than one. All inpatients were exposed to various medical interventions such as intensive care (44%), mechanical ventilation (41%), haemodialysis (25%), Foley’s catheterisation (13%) and central venous lines (6%). Most patients (81%) were in hospital longer than two weeks. The susceptibility rates of S. maltophilia to minocycline (97%), trimethoprim- sulfamethoxazole (93%) and levofloxacin (92%) were high; the rate was lowest for ceftazidime (50%). Conclusion: S. maltophilia was found to be an important nosocomial opportunistic pathogen. Prolonged hospital stay and exposure to various medical interventions were key factors contributing to the development of infection. Minocycline and ceftazidime were found to be the most and least susceptible drugs, respectively. Keywords: Nosocomial Infection; Opportunistic Infections; Fluoroquinolones; Hemodialysis; Ventilation; Oman. امللخ�ص: الهدف: الستينوتروفوموناس مالتوفيليا ، هي ع�صيات غري خممرة �صالبة اجلرام، ظهرت كمر�ض ميكروبي مهم يف امل�صت�صفيات يف ال�صنوات االأخرية. وهذه البكرتيا لديها مقاومة للعديد من امل�صادات احليوية ولديها القدرة على اكت�صاب مقاومة للمضادات احليوية باآليات متعددة. لذلك ، فاإن علج عدوى الستينوتروفوموناس مالتوفيليا ميثل حتدًيا خطرًيا للأطباء. هدفت هذه الدرا�صة اإىل التحقق من اأمناط احل�صا�صية مالتوفيليا. الطريقة: اأجريت درا�صة م�صتعر�صة ا�صرتجاعية يف للم�صادات احليوية وعوامل اخلطر التي ت�صهم يف عدوى الستينوتروفوموناس م�صت�صفى �صحار، عمان. متت مراجعة البيانات الدميوغرافية وال�رسيرية وامليكروبيولوجية للأفراد الذين مت عزل الستينوتروفوموناس مالتوفيليا فيهم خلل الفرتة بني �صبتمرب 2016 واأغ�صط�ض 2019. مت عمل االإح�صاء الو�صفي على �صكل تكرارات ون�صب مئوية. النتائج: متت درا�صة ما جمموعه 41 عزلة من الستينوتروفوموناس مالتوفيليا من العينات ال�رسيرية لـ 14 مري�صا. حدثت العدوى يف الغالب عند الذكور )%73( وكانت غالبية املر�صى )%88( مابني عمر خم�ض �صنوات و 60 �صنة. كان لدى جميع املر�صى املرقدين مر�ض مزمن واحد على االأقل بينما كان لدى %50 اأكرث من واحد. تعر�ض جميع املر�صى املرقدين لتدخلت طبية خمتلفة مثل العناية املركزة )%44(، والتهوية امليكانيكية )%41(، والغ�صيل الكلوي )%25(، وق�صطرة فويل )%13( واخلطوط الوريدية املركزية )%6(. بقي معظم املر�صى )%81( يف امل�صت�صفى ملدة تزيد عن اأ�صبوعني. كانت معدالت ح�صا�صية الستينوتروفوموناس مالتوفيليا للمينو�صيكلني )%97(، و الرتمييثوبرمي-�صلفاميثوك�صازول )%93( والليفوفلوك�صا�صني )92%( وهي ن�صب مرتفعة. كانت احل�صا�صية لعقارل�صيفتازيدمي يف املعدل االأدنى )%50(. اخلال�صة: ال�صتينوروفومونا�ض مالتوفيليا هي اأحد م�صببات االأمرا�ض االنتهازية يف امل�صت�صفيات. كانت االإقامة املطولة يف امل�صت�صفى والتعر�ض للتدخلت الطبية املختلفة من العوامل الرئي�صية التي �صاهمت يف حدوث العدوى. وجد اأن املينو�صكلني اأكرث االأدوية تاأثريعلى هذه البكترييااوال�صيفتازيدمي هو االأقل على التوايل. الكلمات املفتاحية: عدوى امل�صت�صفيات؛ العدوى االنتهازية؛ الفلوروكينولونات؛ غ�صيل الكلى؛ التنف�ض؛ عمان. Stenotrophomonas maltophilia An emerging opportunistic nosocomial pathogen in a tertiary care hospital in Al Batinah North Governorate, Oman *Mohan B. Sannathimmappa,1 Vinod Nambiar,1 Rajeev Aravindakshan,2 Nashwa M. Al-Kasaby3,4 clinical & basic research Sultan Qaboos University Med J, February 2021, Vol. 21, Iss. 1, pp. e66–71, Epub. 15 Mar 21 Submitted 26 Feb 20 Revisions Req. 16 Apr & 21 May 20; Revisions Recd. 27 Apr & 21 May 20 Accepted 25 Jun 20 https://doi.org/10.18295/squmj.2021.21.01.009 This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License. Advances in Knowledge - Stenotrophomonas maltophilia infection predominantly occurred in males and in the younger and older age groups. - S. maltophilia have shown good susceptibility to all tested antibiotics. - S. maltophilia was most sensitive to minocycline and least susceptible to Ceftazidime. https://creativecommons.org/licenses/by-nd/4.0/ Mohan B. Sannathimmappa, Vinod B. Nambiar, Rajeev Aravindakshan and Nashwa M. Al-Kasaby Clinical and Basic Research | e67 Application to Patient Care - Incidence, risk factors and pattern and rate of antimicrobial resistance among S. maltophilia strains vary widely between regions. Regularly determining the prevalence of S. maltophilia and antibiotic resistance patterns and updating physicians' knowledge regarding this opportunistic organism will result in better management of S. maltophilia infection. - Patients would benefit in terms of controlling antimicrobial resistance, reducing treatment failure and lessening mortality rates and financial burden. Stenotrophomonas maltophilia, formerly known as Xanthomonas maltophilia, is an aerobic, non-fermentative Gram-negative bacillus (NFGNB), widely distributed in almost all humid environments including hospital settings.1–3 It survives on almost any humid surface and has been isolated from hospital equipment and supplies including mechanical ventilators, heart-lung machines, indwelling devices (i.e. endotracheal tubes, central venous and urinary catheters), haemodialysis units, endoscopes, nebulisers, disinfectants, hand wash solutions and intravenous fluids.4–7 Although generally considered an asymptomatic coloniser or organism of low virulence, S. maltophilia has evolved in the past two decades to become an important opportunistic nosocomial pathogen, especially in critically ill patients.8–13 Bypassing natural body defences is pivotal for the development of Stenotrophomonas infections.1–7 The infections are particularly common among very young and very old immunocompromised individuals and in patients with chronic respiratory illness, cystic fibrosis, neutropaenia and other immunodeficiency disorders.4,7–10 The risk factors for S. maltophilia infection include prolonged mechanical ventilation, use of indwelling devices, previous exposure to broad-spectrum antibiotics and parenteral nutrition therapy.4,6–8 S. maltophilia is the third most common NFGNB associated with nosocomial infections next to P. aeruginosa and Acinetobacter baumannii.11 It is associated with a wide range of infections with pneumonia and bloodstream infections being the two most common manifestations.14 Meningitis, brain abscess, urinary tract infection, skin and soft tissue infection, endocarditis and ocular and ear infections are less frequently seen infections caused by S. maltophilia.1,4,5,7 S. maltophilia-associated infections pose serious treatment challenges because they are intrinsically resistant to many antibiotics including aminoglycosides and carbapenems and the bacillus has the ability to acquire resistance to antimicrobial agents by multiple mechanisms.4,14,15 Numerous studies have reported trimethoprim-sulfamethoxazole (TMP-SMX) as the antibiotic of choice for treating S. maltophilia infections.14–16 Fluoroquinolones, minocycline and ceftazidime were also found to be effective drugs.4,16–18 However, recent studies have reported alarming increases in the resistance of Stenotrophomonas to these agents.1,12 Furthermore, its ability to form biofilm and quorum sensing has posed treatment challenges especially in critically ill patients in intensive care units (ICUs).1,9,15 There is a paucity in the literature of studies on S. maltophilia in Al Batinah North governorate, Oman. Hence, the present study aimed to investigate the antimicrobial susceptibility of S. maltophilia isolated at Sohar Hospital’s Microbiology Laboratory, Sohar, and reveal related clinical backgrounds such as the spectrum of infection, comorbidity and underlying risk factors contributing to infection. Methods This retrospective cross-sectional study was cond- ucted at a 400-bed referral ministry hospital in Al Batinah North governorate, Oman. The clinical and microbiological data of 41 S. maltophilia isolates that grew from clinical samples from September 2016 to August 2019 were retrieved from microbiology laboratory records and the Al-Shifa electronic medical records system. The collected information included patients’ demographic characteristics, length of hospital stay, comorbidities at the time of admission, exposure to medical equipment and instruments, site of infection and the type of clinical specimen processed in the laboratory. All the strains of S. maltophilia isolated from sterile sites such as blood and cerebral spinal fluid and the strains isolated from sites such as skin, mucus membranes, wounds and endotracheal tubes in the presence of clinical signs and symptoms were considered infections and included in the study. S. maltophilia isolated from non-sterile sites such as skin, mucus membranes, wounds and endotracheal tubes in the absence of clinical signs and symptoms were considered colonisation and excluded from the study. Repeat isolates from all clinical samples were excluded. S. maltophilia isolates were recovered from different clinical samples including blood, urine and respiratory secretions. The isolates were identified by standard microbiological methods and the automated Vitek® 2 system (bioMérieux SA, Lyon, France). Stenotrophomonas maltophilia An emerging opportunistic nosocomial pathogen in a tertiary care hospital in Al Batinah North Governorate, Oman e68 | SQU Medical Journal, February 2021, Volume 21, Issue 1 Antimicrobial susceptibility testing was performed using Kirby-Bauer's disc diffusion method on Mueller- Hinton agar with the following antibiotic panel by using Oxoid™ antibiotic susceptibility disks (Thermo Fisher Scientific, Waltham, Massachusetts, USA): levofloxacin (5 μg), TMP-SMX (1.25/23.75 μg) and minocycline (30 µg). For ceftazidime, a minimum inhibitory concentration was determined by the Epsilometer test (Etest), as recommended by the Clinical Laboratory Standards Institute.19 Quality control was performed using Escherichia coli (ATCC 25922) and P. aeruginosa (ATCC 27853). The data obtained were entered and analysed using Statistical Package for Social Sciences (SPSS), Version 22 (IBM, Corp., Armonk, New York, USA). Descriptive statistics for all variables were derived using Epi Info 7 for Windows (Centers for Disease Control and Prevention, Atlanta, Georgia, USA) and stated mainly as frequency and percentages. Antibiotic susceptibility was interpreted as sensitive or resistant. This study was approved by the Research and Ethical Committee of the Ministry of Health in Oman (MH/DHSG/NBG/1923195718/2019). Table 1: Demographic and clinical characteristics of patients infected with Stenotrophomonas maltophilia at a tertiary care hospital in Al Batinah North Governorate, Oman (N = 41) Characteristic n (%) Age in years <1 7 (17) 1–5 7 (17) 6–30 0 (0) 31–60 5 (12) >60 22 (54) Gender Male 30 (73) Female 11 (27) Duration of hospital stay (n = 32) <2 days 2 (6) 3–7 days 4 (13) 2–4 weeks 11 (34) >4 weeks 15 (47) Source/site of organism isolation* Respiratory secretions 15 (37) Blood 13 (32) Urine 5 (12) Wound/pus swab 3 (7) Eye swab 2 (5) Ear swab 1 (2) Synovial fluid 1 (2) Cerebrospinal fluid 1 (2) *Six S. maltophilia strains were isolated from the clinical samples received from other hospitals, and three strains were isolated from the patients treated in the outpatient department Table 2: Comorbidity and underlying risk factors of in- patients with Stenotrophomonas maltophilia infection at a tertiary care hospital in Al Batinah North Governorate, Oman (N = 32) Comorbidity/Risk factor n (%) Presence of one comorbidity 32 (100) Presence of more than one comorbidity 16 (50) Type of cormobidity Cardiovascular diseases (hypertension, IHD, CHD, etc.) 16 (50) Chronic renal diseases (end stage renal disease) 9 (28) Pulmonary diseases 8 (25) Diabetes 8 (25) Congenital/inherited diseases* 7 (22) CNS disorders 5 (16) Liver cirrhosis and oesophageal varices 1 (3) Underlying risk factor ICU admission 14 (44) Mechanical ventilation 13 (41) Haemodialysis 8 (25) Foley’s catheterisation 4 (13) Central venous line 2 (6) Length of hospital stay >two weeks 26 (81) IHD = ischaemic heart disease; CHD = congenital heart disease; CNS = central nervous system; ICU = intensive care unit. *One patient each had cystic fibrosis, Guillain-Barré syndrome, Hirschprung’s disease, cerebral palsy, Dandy Walker’s disease, Krebs’ disease and con- genital heart disease. Table 3: Antibiotic susceptibility pattern of Stenotroph- omonas maltophilia Antibiotic Antibiotic susceptibility in % Sensitive Resistance TMP-SMX 93 7 *Ceftazidime 50 50 Levofloxacin 92 8 Minocycline 97 3 TMP-SMX = trimethoprim-sulfamethoxazole. *Antibiotic sensitivity tested by Epsilometer test. Mohan B. Sannathimmappa, Vinod B. Nambiar, Rajeev Aravindakshan and Nashwa M. Al-Kasaby Clinical and Basic Research | e69 Results A total of 41 S. maltophilia isolates from various clinical samples received at Sohar Hospital’s Microbiology Laboratory were reviewed. S. maltophilia was predominantly isolated from males (73%) compared to females (27%). The majority of the patients (88%) were ≤five years old (34%) or >60 years old (54%). Most patients (78%) were inpatients and had a hospital stay of at least two weeks (81%) [Table 1]. All inpatients had one comorbidity while 50% had more than one comorbid conditions such as cardiovascular disease (50%), chronic renal disease (28%), pulmonary disease (25%), diabetes (25%), congenital/inherited diseases (22%) or central nervous system disorders (16%). All inpatients had undergone medical interventions including being admitted to the intensive care unit (44%), mechanical ventilation (41%), haemodialysis (25%), Foley’s catheterisation (13%) or the insertion of central venous lines (6%). With respect to the source, S. maltophilia was isolated most frequently from blood (32%) followed by endotracheal secretions (24%), sputum (12%), urine (12%), swabs of wounds (7%), eyes (5%) and ears (2%) and synovial (2%) and cerebrospinal (2%) fluid [Table 2]. In the present study, the in vitro susceptibility rate of S. maltophilia was highest for minocycline (97%) followed by TMP-SMX (93%) and levofloxacin (92%). However, only 50% of S. maltophilia samples showed resistance to ceftazidime [Table 3]. Discussion S. maltophilia, previously considered a coloniser, has emerged as an important nosocomial pathogen within the past few decades, especially in severely immunodeficient individuals. It can cause serious infections and treating these associated infections can pose a serious challenge because of limited therapeutic options and the rapid development of antimicrobial resistance. The present study investigated antibiotic susceptibility patterns as well as underlying risk factors in patients who acquired S. maltophilia infections. The present study observed a predominance of S. maltophilia isolation from males. Most patients had either an immature or weakened immune system and were ≤5 or >60 years of age (88%); these findings were consistent with previous studies.7,8 Additionally, all patients had one (100%) while some (50%) had more than one comorbidity such as pulmonary or chronic kidney disease, diabetes or congenital/inherited disorders. In a similar study, Kim et al. demonstrated the association of S. maltophilia infection with a variety of comorbid conditions.20 An important feature of S. maltophilia is its ability to asymptomatically colonise biotic or abiotic surfaces due to the formation of biofilm rather than infection, which is often associated with an individual’s decreased immune status.18,20 Invasive procedures (e.g. mechanical ventilation, central venous line, Foley’s catheterisation and haemodialysis), receiving medical attention in intensive care facilities, prolonged length of hospital stay (more than two weeks), exposure to broad-spectrum antibiotics and immunocompromised status were found to be key underlying risk factors for S. maltophilia infections.18,20 Risk factors in the present study group were similar to previous reports.1,12,21 S. maltophilia has developed extensive resistance to most commonly used antibiotics including beta- lactams, cephalosporins and macrolides and is intrins- ically resistant to carbapenems and aminoglycosides.22 Susceptibility data are available for a limited number of antimicrobial agents such as TMP-SMX, fluoroquin- olones such as levofloxacin and moxifloxacin, ceftazi- dime, minocycline and doxycycline.14–15 In the present study, most isolates (93%) were found to be susceptible to TMP-SMX. This finding is in line with but slightly lower than reports from Ismail et al. where all strains tested with an Etest showed susceptibility to TMP-SMX.14 However, resistance rates, are increasing and 7% of strains showed resistance to TMP-SMX in the present study. This low-level resistance (2–10%) is in accordance with many previous studies.9,14,23 A few outliers, however, have demonstrated high levels of resistance ranging from 10–25%.7,24–26 TMP-SMX, therefore, can still be recommended as the first-line drug for empirical therapy of S. maltophilia infections. Fluoroquinolones have become reasonable alter- natives to treat Stenotrophomonas infections. Reports have shown that monotherapy with fluoroquinolones achieves equal efficacy to TMP-SMX.26,27 The findings of the present study were consistent with many other studies that demonstrated potent in vitro susceptibility of fluoroquinolones against S. maltophilia.26,27 In the present study, 92% of the strains demonstrated susceptibility to levofloxacin. This finding was slightly lower than was found in a study by Wu et al. in which all strains isolated from ocular infections were susceptible to levofloxacin and moxifloxacin.26 However, several studies have revealed a resistance rate ranging from 10–50% to fluoroquinolones.14,24,28,29 Hence, it is imperative to select antibiotics to treat S. maltophilia infection based on local antimicrobial sensitivity patterns. The clinical value of levofloxacin is greater as it has the advantage of biofilm disruption and achieving much higher concentrations than the minimum inhibitory concentration, especially in respiratory secretions.5,14,24 These advantages make Stenotrophomonas maltophilia An emerging opportunistic nosocomial pathogen in a tertiary care hospital in Al Batinah North Governorate, Oman e70 | SQU Medical Journal, February 2021, Volume 21, Issue 1 levofloxacin a better choice among quinolones, esp- ecially to treat respiratory infections. In the present study, most of the S. maltophilia isolates (97%) showed in vitro susceptibility to minocycline. This finding is in concordance with the results of Looney et al.11 However, the clinical use of minocycline is still limited due to its ototoxicity, although it is highly effective against Stenotrophomonas.11 Among beta-lactams, anti-pseudomonal beta- lactams such as ceftazidime were previously cons- idered to be the most effective drugs against S. malto- philia.30 However, recent studies have demonstrated a high rate of resistance (>40%) to these antibiotics.24,31,32 The present study results were congruent with the results of those studies, where half of the Stenotro- phomonas strains showed resistance to these drugs, suggesting increased global resistant trends to ceph- alosporins.24,31,32 Owing to the rapid emergence of drug-resistant strains of Stenotrophomonas for monotherapy (with TMP-SMX, fluoroquinolones and other drugs), combination therapy with two or three antibiotics, especially in critical patients with serious infections, have been proposed by several researchers as a way to attain synergism and overcome drug resistance.14,15 Gregory et al. demonstrated better in vitro bactericidal effects when using a combination of TMP-SMZ and moxifloxacin on S. maltophilia when compared to monotherapy.15 Although there are not enough data on the in vivo efficacy of combination therapy, several studies have suggested the use of a combination of drugs for treating severe invasive infections, especially in immune-deficient individuals.12,14,15 The present study was subject to certain limitations. First, the sample size was small. Second, the study did not assess the prior antibiotic exposure and treatment outcomes of infected patients. Third, this study was retrospective; therefore, the culture results were not clinically correlated to determine whether they represented infection or colonisation accurately. Finally, this was a single-centre study in Oman; hence, the findings may not be generalisable. Conclusion S. maltophilia is an important emerging nosocomial opportunistic pathogen. Prolonged length of hospital stay and exposure to various invasive medical inter- ventions were key factors contributing to infection. TMP-SMZ, levofloxacin and minocycline showed good in vitro susceptibility against S. maltophilia and are promising therapeutic options. a c k n o w l e d g e m e n t s The authors express their sincere appreciation to all the microbiology laboratory and information and technology staff of Sohar Hospital for their kind- hearted support. The authors would also like to thank Dr. Ali Al-Maqbali, Research Head RERAC, North Batinah, for his valuable feedback and continuous support. 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. Adegoke AA, Stenström TA, Okoh AI. Stenotrophomonas maltophilia as an emerging ubiquitous pathogen: Looking beyond contemporary antibiotic therapy. Front Microbiol 2017; 8:2276. https://doi.org/10.3389/fmicb.2017.02276. 2. Satish M, Mumtaz MA, Bittner MJ, Valenta C. Stenotro- phomonas maltophilia endocarditis of an implantable cardio- verter defibrillator lead. Cureus 2019; 11:e4165. https://doi.org/10.7 759/cureus.4165. 3. Geller M, Nunes CP, Oliveira L, Nigri R. S. maltophilia pneumonia: A case report. Respir Med Case Rep 2018; 24:44–5. https://doi.org/10.1016/j.rmcr.2018.04.004. 4. Xun M, Zhang Y, Li BL, Wu M, Zong Y, Yin YM. 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