INCIDENCE OF ANTIBIOTICS RESISTANCE OF UROPATHOGENS IN OMANI CHILDREN PRESENTED WITH SINGLE EPISODE OF URINARY TRACT INFECTION Mohamed El-Naggari 1, Sharef Waadallah 2, Dana Al Nabhani 1, Ali Al Sawai 2 Zakaria Al Muharrmi 3, Ibtisam El Nour 1. Sultan Qaboos University Hospital; Pediatric Nephrology (1), General pediatric. (2) Sultan Qaboos University ; Microbiology Department. (3) Muscat; Sultanate Of Oman. Corresponding Author: mnaggari@yahoo.com ; mnaggari@squ.edu.om. Abstract Results Urinary tract infection (UTI) is one of the most common community-acquired infections. Different organisms can be the cause of UTI in children, with resistance to antibiotics becoming a significant problem in the choice of treatment. Worldwide studies have documented the prevalence of uropathogens in different countries. However, there is no previous study documenting the incidence of different uropathogens in Oman. We aim to report the most common uropathogens, and their antibiotic sensitivity pattern, in children presented with documented single episode UTI, at a tertiary hospital in Oman. A retrospective analysis of all Omani children below 14 years presented with first documented UTI, to SQUH between September 2008 and August 2012. On retrospective review of all urine cultures, 438 positive urine cultures were identified. Out of those 208 (47.5%) belonged to children with first episode of UTI. 33 patients were excluded and 175 patients were finally analyzed. E. coli was the most frequently encountered uropathogen in our cohort (69%) followed by Klebsiella Pneumonia infection (17%). 46.6 % of these two common organism were resistant to cotrimoxazole while 31% of them were resistant to Augmentine. 24% of E. coli and K. Pneumonia were resistant to Cefuroxime & only 10 % were resistant to Nitrofurantoin. Both Augmentine and Cotrimexazole should not be the first line antibiotics to treat UTI. Between September 2008 and August 2012, 438 urine samples grew significant bacteria. Only 208 positive urine cultures belonged to 208 patients with first incidence of urinary tract infection. 33 patients were excluded from the study; 11 with neurological disabilities, 9 with hematological malignancy, 3 with immune deficiencies and 10 were excluded for deficiency of data. In our studied patients, UTI was widely distributed in all age groups, however, the largest proportion was in those <1 year of age (46 patients, 26%), (Table 1). Laboratory Finding All (total =175) ≤ 2 years (n=61) 2-14 yrs (n=114) P value WBC ( In 131 patients) Leukocytosis *, n (%) WBC (x10^9/L), range WBC (x10^9/L), mean (±SD) (n=131) 31 (24%) 2-31 11.9(±5.7) (n=51) 10 (20%) 5-31 13.5(±6) (n=80) 21 (18%) 2-28 10.8(±5.3) 0.100 ANC (In 131 patients) (x10^9/L) Neutrophilia *, n (%) Neutrophil count, range Neutrophil count, mean (±SD) 38 (29%) 1-24 6.2 (±4.7) 13 (25%) 1-18 5.7 (±4.6) 25 (22%) 6.4 (±4.8) 0.115 CRP (In 73 patients) High CRP **, n (%) CRP range CRP count (mg/L), median (IQR) (n=73) 51 (70%) 2-319 24 (3-99) (n=30) 18 (60%) 1-319 32 (12-99) (n=43) 33 (29%) 3-282 37 (9-125) 0.098 Urinary WBC (In 175 patients) Positive urinary WBCs, n (%) WBC count / cmm, Median (IQR) (n=175) 88 (50%) 75 (25-500) 23 (38%) 500 (75-500) (n=114) 65 (57%) 0.015 0.040 Urinary RBC (In 175 patients) Microscopic haematuria, n (%) RBC count / cmm, Median (IQR) 53 (30%) 50 (10-50) 17 (28%) 36 (32%) 0.611 0.900 Nitrite (In 82 patients) Positive urinary nitrate, n (%) (n=82) 29 (35%) (n=31) 7 (23%) 22 (43%) 0.118 Table 2 shows the cultured pathogens among the studied 175 patients with community acquired UTI. The most common isolated pathogen was Escherichia coli (77%), followed by Klebsiella spp (10%), Enterobacter spp (9%). Overall resistance to oral antibiotics was highest to Ampicillin (75%), followed by Cotrimoxazole © (Trimethoprim/Sulfamethoxazole; TMS) (47%), Augmentin© (amoxicillin/clavulanate) (43%). Overall resistance to IV antibiotics was less evident than oral antibiotics.Three out of the 120 isolated E coli (3%) and two out of the 30 isolated Klebsiella spp (7%) were Extended-Spectrum Beta-Lactamases (ESBL). Sex distribution n (%) Age (years) Female, n (%) Male, n (%) 15 (33%) 31 (67%) 46 (26%) < 1 year 10 (67%) 5 (33%) 15 (9%) >1 yr to 2 yrs 30 (81%) 7 (19%) 37 (21%) > 2 yrs to 5 yrs 35 (95%) 2 (5%) > 5 yrs to 8 yrs 37 (92%) 3 (8%) 40 (23%) > 8 yrs to 14 yrs 127 (73%) 48 (27%) 175 (100%) TOTAL Introduction Urinary tract infection (UTI) is a common cause of fever and one of the most common community-acquired infections. Due to possible complications of upper UTI (pyelonephritis) such as renal scarring, hypertension, and end-stage renal disease, treatment with proper antibiotic is a crucial step of management. Although children with pyelonephritis tend to have fever and more systemic features, it is often difficult to distinguish cystitis from pyelonephritis based on clinical presentation, particularly in those younger than two years of age. (1) Different organisms can be the cause of UTI in children, with resistance to antibiotics becoming a significant problem in the choice of treatment. Frequent use of wide-spectrum antibiotics may change the intestinal flora, and as a consequence, induce bacterial resistance. Regular surveillance of local uropathogens as well as their antibiotic susceptibility is considered useful to guide empirical therapy, as the prevalence of uropathogens and their features may vary according to the time and geographical area. (2) The American Academy of Pediatrics, the Royal College of Physicians of London and the National Guideline Clearing house recommend empirical and precocious treatment of UTI, based on the susceptibility standard to the antibiotics that are habitually utilized, with the objective of reducing risks of pyelonephritic scarring.(3) Worldwide studies have documented the prevalence of uropathogens in different countries. (4,5) However, there is no previous study documenting the incidence of different uropathogens in Oman. In this study, we aim to report the most common uropathogens, and their antibiotic sensitivity pattern, in children presented with documented single episode UTI, at a tertiary hospital in Oman. In addition, we aim to describe the clinical presentation and laboratory evaluation in those children. Table 1: Age and sex distribution of children with UTI (n=175) Table 4: Laboratory findings in patients with UTI. Resistance (%) Antibiotic Strept agalactiae n=1(0.6%) Staph spp n=4(2%) Citrobacter n=3 (2%) Enterobacter Pseudomonas n=2 (1%) Entero- coccus n=7 (4%) Klebsiella spp ** n=30(17%) E coli spp* n=120 (69%) ALL n= 175 (100%) 25 100 76 75 Ampicillin 23 24 43 Augmentin 85 4 Amikacin 10 18 14 Ciprofloxacin 33 71 7 Cefotaxime Ceftriaxone 67 17 19 21 Cefuroxime 13 2 Nitrofurantoin 11 Gentamicin 1 Meropenem 80 20 50 47 Cotrimoxasole # Tazocin @ Table 2: Percentage of antibiotic resistance of the isolated uropathogens (n=175). * 3 out of the 120 isolated E coli (3%) were Extended-Spectrum Beta-Lactamases (ESBL) E coli. ** 2 out of the 30 isolated Klebsiella (7%) were Extended-Spectrum Beta-Lactamases (ESBL) Klebsiella pneumoniae. # Cotrimoxasole = Trimethoprim/Sulfamethoxazole. @ Tazocin = Piperacillin/Tazobactam. Methods Conclusions A retrospective analysis of all Omani children with the first documented UTI, who presented to Sultan Qaboos University Hospital (SQUH) over 4 years duration between September 2008 and August 2012. All patients below 14 years of age with positive urine culture were evaluated for inclusion in the study. Exclusion criteria included: patients with recurrent UTI, neurological impairment (bed ridden patients), immune deficiencies and hematological malignancies, as these patients might have recurrent UTI or recurrent exposure to antibiotics which may affect the antibiotic resistance pattern. Patients with deficient data were also excluded from the study. Data collected included age, gender, and clinical presentation such as fever, chills, , decreased activity, nausea and/or vomiting, abdominal pain, poor feeding, constipation, frequency or urination, dysuria, flank pain, secondary enuresis, gross haematuria and foul-smelling urine. Other data included method of urine collection, results of urine analysis including nitrites, pyuria and haematuria, in addition to results of urine culture and antibiotic sensitivity. Laboratory parameters included presence of leukocytosis, neutophilia, high CRP. Pyuria was defined as ≥5 WBC/high power field (HPF) and classified as mild 5-20, moderate 20-60 and severe >60 WBC/HPF respectively. Haematuria was defined as 5 RBCs per HPF, and classified as gross or microscopic. Urine culture method: In clean catch samples, significant bacteriuria was defined as growth of ≥100,000 colony forming units (CFU)/mL of a single uropathogenic bacteria. In catheter urine samples, we defined significant bacteriuria as growth of ≥50,000 CFU/mL of a single uropathogenic bacteria. (7) Data was entered in SSPS. Analysis included the distribution of UTI among different age group and gender categories. Different uropathogens causing UTI and their antibiotic sensitivity were reported. Descriptive statistics were used including frequencies and percentages for categorical variables, in addition to mean (± standard deviation) or median (and interquartile ratio IQR) for numerical variables. Differences between different groups were analyzed using Chi-squared (χ2) test or student’s t-test and Wilcoxon-Mann-Whitney test as appropriate. An a priori two-tailed level of significance was set at 0.05. P value 2-14 yrs (n=114) ≤ 2 yrs (n=61) All (n=175) Medical history 0.003 0.406 48 (42%) 38.8 (±0.9) 40 (66%) 38.6 (±0.7) 88 (50%) 38.7 (±0.8) Fever, n (%) Degree of temp. , Mean (± SD) 0.069 0.087 10 (9%) 8 (7%) 2 (2%) 11 (18%) 3 (5%) 0 (0%) 21 (12%) 11 (6%) 3 (2%) Fever only, n (%) Fever > 40 degrees, n (%) Chills, n (%) 0.002 36 (32%) 34 (56%) 70 (40%) Nausea and/or Vomiting, n (%) <0.001 51 (45%) 51 (29%) Abdominal pain, n (%) 41 (36%) 4 (7%) 45 (26%) Frequency, urgency, dysuria, n (%) 6 (6%) 13 (21%) 20 (11%) Reduced / Poor feeding, n(%) 6 (5%) 15 (25%) Decreased activity, n (%) 0.048 7 (6%) 7 (4%) Flank pain, n (%) 0.034 8 (5%) Secondary enuresis, n (%) 0.068 6 (3%) Gross haematuria, n (%) 0.244 1 (2%) Foul-smelling urine, n (%) 0.936 4 (4%) 2 (3%) Constipation, n (%) UTI was found to be more prevalent in female gender. E. coli was the most frequently encountered uropathogen in our cohort. While we observed high resistance to oral Cotrimoxazole in uropathogens found in our study compared to other reports, resistance to IV antibiotics (including Tazocin, gentamycin, cefotaxime, and ceftriaxone) was much less. We recommend that use of Ampicillin, Augmentin and Cotrimoxazole could not be justified as a first line of treatment, specifically in patients with acute pyelonephritis. If these antibiotics are used, patients should be reviewed within 48 hours with sensitivity report and determine further therapy. The reported antibiotic sensitivity may help in the future choice of antibiotic therapy, however, a larger multi center national study is recommended to establish wider description of the prevalent uropathogens in Oman. References 1. 1. Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, Wald ER. Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med 2003; 348:195-202. 2. Livermore DM,Pearson A. Antibiotic resistance: location, location, location.Clin Microbiol Infect 2007; 2: 6-17. 3. American Academic of Pediatric. Committee on Quality Improvement. Subcommittee on Urinary Tract Infections. Practice parameter: The diagnosis, treatment and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 1999;103:843-52. 4. Magliano E, Grazioli V, Deflorio L, Leuci A, Mattina R, Romano P, et al. Gender and Age-Dependent Etiology of Community-Acquired Urinary Tract Infections. ScientificWorldJournal. 2012; 2012: 349597. 5. Ghorashi Z, Ghorashi S, Soltani-Ahari H, Nezami N. Demographic features and antibiotic resistance among children hospitalized for urinary tract infection in northwest Iran. Infect Drug Resist 2011;4: 171–176. 6. Kass EH. Asymptomatic infections of the urinary tract. Trans Assoc Am Physicians 1956; 69: 56-64. 7. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011; 128: 595-610. Table 3: Medical history in patients with UTI among different age. (Table 3) Fever was the most common symptom presenting in 88 (50%) children, but fever as the only presenting symptom was documented in 21 (12%) of the patients. Fever, vomiting, and poor feeding were more significantly the presenting symptoms in children ≤ 2 years of age, abdominal pain, flank pain, and urinary symptoms were more frequently reported in those > 2 years of age. Among the 131 patients who had full blood count tested, leukocytosis was reported in 31 patients (24%), and neutrophilia in 38 Patients (29%) (mean WBC count 11,900 ± 5700/mm3, mean absolute neutrophil count 6,200 ±4,700/mm3). (Table 4) High CRP was documented in 51 (70%) of the 73 patients who had this test, with a median (IQR) of 24 (3-99). There was no significant difference in inflammatory markers between children ≤ 2 years and those > 2 years of age.