MULTIDRUG RESISTANT URINARY TRACT INFECTION IS KLEBSIELLA SPP THE FIRST ENEMY TO FIGHT WITH?

Rev. Med. Chir. Soc. Med. Nat., Iaşi 2017 vol. 121, no. 2 PREVENTIVE MEDICINE - LABORATORY ORIGINAL PAPERS MULTIDRUG RESISTANT URINARY TRACT INFECTION IS KLEBSIELLA SPP THE FIRST ENEMY TO FIGHT WITH? D. Puia 1 *, Adelina Miron 1, S. Gheorghinca 1, Ancuta-Vasilica Puia 2, C. Pricop 1 Grigore T. Popa University of Medicine and Pharmacy Iasi Faculty of Medicine 1. Department of Surgery (II) Sf. Maria Children s Hospital Iasi 2. Department of Microbiology *Corresponding author. E-mail: drdragos83@yahoo.com MULTIDRUG RESISTANT URINARY TRACT INFECTION - IS KLEBSIELLA SPP. THE FIRST ENEMY TO FIGHT WITH? (Abstract): Klebsiella spp is the second causative bacteria of urinary tract infection. Aim: To identify the profile of urological patients with Klebsiella spp. urinary tract infection. Material and methods: Review of the medical records of all patients with multidrug resistant urinary tract infection (MDR-UTI) admitted to the Iasi Urology Clinic between 2013 and 2016. Results: A total number of 753 patients with Klebsiella spp.-positive urine culture aged 18 to 95 years, mean age of 66.3 years were included in the study. The elderly was the age group most affected by Klebsiella spp. UTI. One quarter (25.89%) of patients had a neoplasm history and one third (31.07%) poor hygiene conditions. Almost one quarter of patients (24.70%), had a history of antibiotic use in the last three months and 520 patients had different urinary stents, most frequently bladder catheter (n=385). Klebsiella spp. strains resistance to penicillin was 40-99%, to cephalosporins 38-88%, fluoroquinolones 85-94%, gentamicin 80%, carbapenemes 21-33%, colistin 66%, Fosfomycin 21%, TMP-SMX 90% and to Piperacilin 75%. Conclusions: MDR-UTI due to Klebsiella spp. remains a challenge for clinicians both in terms of treatment and prevention. Keywords: KLEBSIELLA, ANTIBIOTIC RESISTANCE, UTI. Urinary tract infections (UTIs) are one of the most common microbial diseases encountered in medical practice affecting people of all ages are. Worldwide, the prevalence of UTIs was estimated to be around 150 million persons per year (1). It is well known that UTI is the single most common hospital-acquired infection. While traditionally the most commonly encountered bacteria in UTI is E. coli, Klebsiella spp. is well-known as a causative agent of both community and hospital acquired pneumonia, bacteremia, and UTIs. In large epidemiological studies Klebsiella spp is the second most common causative bacteria of UTI (1, 2). Besides its high incidence we need to better understand this pathogen because of the increase in the number of vulnerable patients and in antibiotic resistance. The aim of our study was to identify the profile of urological patients with Klebsiella spp. UTI. MATERIAL AND METHODS In this prospective study, the medical records of all patients with multidrug re- 366

Multidrug resistant urinary tract infection is Klebsiella spp the first enemy to fight with? sistant urinary tract infection (MDR-UTI) admitted and treated to the Iasi Urology Clinic between January 1 st, 2013 and January 1 st, 2016 were reviewed. We considered MDR-UTI those urine cultures with bacteria resistant to more than 3 antibiotics of different classes or all antibiotics of a single class, regardless of the urological and other comorbidities (3). Data on age, sex, prior antibiotic treatment in the last three months, the presence of a urinary catheter, history of recurrent cystitis, menopause, habitual constipation and diabetes mellitus were collected. We have also evaluated the possibility of proper hygiene through the availability of running water and indoor toilet facilities at home. Statistical analysis was made using Student t-test for 2 Independent Means and Chi-Square test, calculated online on http://www.socscistatistics.com/tests/defau lt.aspx, statistical significance was defined as p value 0.05. RESULTS Between 2012-2016, 1742 patients, 1171 (67.22%) men and 571 (32.77%) women aged 18-95 years, mean age 65.05 years (SD=14.69) were diagnosed in our clinic with UTI. Although we expected that E. coli, to be most frequently identified bacteria, Klebsiella spp. - 43.22% (n=753) was the most commonly isolated bacteria, followed by E. coli - 20.78%, Pseudomonas - 14.17%, and other bacteria 21.83%. A total number of 753 patients with Klebsiella spp.-positive urine cultures were included in the study, 506 (67.19%) males and 247 (32.80%) females. The age of patients with Klebsiella spp. UTI ranged from 18 to 95 years, with a mean age of 66.3 years. The mean age of female patients with UTI was 59.76 years, significantly lower than that of the male patients, 68.59 years (p=0.0001, t= 7.64973). The age-group distribution is shown in the Table I. TABLE I Age-group distribution of UTI patients Age 18-30 31-40 41-50 51-60 61-70 >71 n= 753 18 19 46 108 195 367 % 2.3 2.5 6.1 14.3 25.8 48.7 The elderly was the age group most affected by Klebsiella spp. UTI with a frequency of 74.62%. A total of 195 (25.89%) patients had a history of cancer. Bladder cancer (43.07%, n=84) was the most common, followed by prostate cancer (21.02%, n=41) and cervical cancer (19.48%, n=38). The other cancers are shown in the chart below (fig.1). Almost one quarter of patients (24.70%, n=186) had a history of antibiotic use within the last three months. The most frequently used antibiotic was ciprofloxacin (20.43%, n=38), followed by ceftriaxone (17.74%, n=33). Other antibiotics used were amoxicillin + clavulanic acid (8.06%, n=15), Tazocin (8.60%, n=16), cefixime (6.98%, n=13), Cefoperazone + Sulbactam (6.45%, n=12), gentamicin (4.30%, n=8), carbapenems (5.37%, n=10), ceftazidime (3.76%, n=7), colistin (1.61%, n=3), TMP-SMX (2.68%, n=5) and 26 (13.97%) patients could not specify. Other identified predisposing factors were recurrent cystitis (18.06%, n=136), menopause (15.40%, n=116), habitual constipation (9.42%, n=71) and diabetes melli- 367

D. Puia et al. tus (8.36%, n=63). We were surprised to find that almost one third of patients (31.07% (n=234) had no access to running water and 28.41% (n=214) did not have indoor toilets at home. The presence of a urinary stent was identified in 520 patients. The most frequently encountered was the bladder catheter (74.03%, n=385). Elderly patients have a significantly higher rate of a catheter dwelling (p=0.00001, χ 2 =32.1311), as shown in Table II. No. patients 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 Fig. 1 Cancers in the history of the study patients. (Legend: 1-bladder tumor, 2- prostate cancer, 3-cervical cancer, 4- colon cancer, 5- upper urothelial tumor, 6- penile cancer, 7- lymphoma, 8- gastric cancer, 9- lung cancer, 10- breast cancer, 11- ovarian cancer, 12-renal cancer) TABLE II. Distribution of urinary catheters JJ Stent Bladder catheter Cystostomy catheter Nephrostomy Patients <60 years 22 44 1 15 Patients >60 years 76 341 4 17 Total 98 385 5 32 TABLE III. In vitro antibiotic resistance rate of Klebsiella spp. Antibiotic Resistant strain/total urine cultures Percent of resistant stains Ampicillin 742/743 99.86 Ampicillin +Clavulanic acid 525/570 92.10 Amoxicillin+ Clavulanic acid 299/743 40.24 Ceftriaxone 442/497 88.93 Cefuroxime 684/697 98.13 Cefixime 59/167 35.32 Ciprofloxacin 405/473 85.62 Norfloxacin 330/386 85.49 Levofloxacin 32/34 94.11 Piperacillin 393/520 75.57 368

Multidrug resistant urinary tract infection is Klebsiella spp the first enemy to fight with? Antibiotic Resistant strain/total urine cultures Percent of resistant stains Gentamicin 581/726 80.02 Imipenem 236/707 33.38 Meropenem 361/730 49.45 Ertapenem 35/166 21.08 Colistin 55/83 66.26 Fosfomycin 7/33 21.21 TMP-SMX 67/74 90.54 Vancomycin 19/20 95 Teicoplanin 25/71 35.21 DISCUSSION Usually, Klebsiella spp. is a bacterium in humans and other mammals, colonizing the gastrointestinal tract, skin, and nasopharynx. According to Tzouvelekis et al. (4), in the early 1970s both the epidemiology and spectrum of infections caused by Klebsiella spp. changed dramatically when this bacterium was established in the hospital environment and became a (still) leading cause of nosocomial infections. Although it produces only moderate amounts of chromosomal penicillinases, Klebsiella spp. is known as a notorious collector of MDR plasmids. In the first decade of the new millennium, a global crisis of unprecedented dimensions was noticed due to the rapid dissemination of MDR Klebsiella spp. strains producing carbapenems encoded by transmissible plasmids. Ramanathan et al. (5) noticed that UTIs account for up to 40% of all healthcareacquired infections and nearly 80% of all UTI occur in patients with short-term urinary catheters and are considered as catheter-associated UTI (CAUTI). In surgical patients, rates of UTI range from 1.8% to 4.1% based on surgery type, and development of UTI is correlated with increased duration of hospital stay and mortality. Traditionally it is considered that women are significantly more likely to experience UTI than men. One third of women will have had at least 1 episode of UTI requiring antimicrobial therapy by the age of 24 years. Almost half of all women will experience one UTI during their lifetime (6). In our study, the men/female ratio was 2:1. This situation can be explained by the fact that our patients did not have community-acquired UTIs, being hospitalized for various urological diseases. This sex ratio is like that reported by Milan et al. (7) in a group of 589 patients, of which only 72 were diagnosed with infection on admission and were classified as CAUTI. Although in our study patient age ranged from 18 to 95 years, we had significantly more old males (54.58%). This finding is not unusual because the incidence of UTI in men without indwelling catheters increases substantially after 60 years of age. According to Schaeffer (9), the incidence of all UTIs among older men is approximately half that among older women, but infection rates among men in the community who are older than 80 years of age approach those among women in the same age range. Older men often have structural and functional abnormalities of the urinary tract such as benign prostatic hyperplasia, which can cause UTI owing to obstruction and impaired urine flow. Moreover, these patients can have comorbidities associated with an increased susceptibility to infection, such as diabetes mellitus. However, in 369

D. Puia et al. our study group only 8.36% of the total number of patients had diabetes mellitus. In our study, a quarter (25.89%) of patients had a cancer history. Most of them (83.58%, n=163) had a pelvic cancer. According to Rolston (9), the factors that increase the risk of infection in neoplastic patients include neutropenia, disruption of anatomic barriers, obstruction due to primary or metastatic tumor, diagnostic/therapeutic surgery, prosthetic devices or advanced age. Obstructive uropathy and complicated UTIs go hand in hand and are often recurrent and difficult to eradicate. In patients with retroperitoneal or pelvic cancers acute or chronic ureteral obstruction is a complication of the malignancy. Prompt decompression of the obstruction is required. For this procedure ureteral stents or, more frequently, percutaneous nephrostomy tubes are used. According to Bahu et al. (10) the use of stents and nephrostomy tubes is associated with a significant rate of pyelonephritis and eradication of such infections is difficult to accomplish. Urinary catheter, especially bladder catheters are only used in neoplastic patients. Older men, as most patients in our study group, often need bladder catheters for urinary retention due to benign prostatic hyperplasia. In our study, of the 385 patients with bladder catheter indwelling, 88.57% were over 60 years of age. According to Ramanathan (5) the presence and duration of catheterization are the strongest risk factors for bacteriuria development. Approximately 10% to 25% patients with bacteriuria progress to symptomatic UTI and 1% to 4% develop urosepsis. In patients with indwelling urinary catheters or in patients with a recent history of indwelling urinary catheterization, the catheter serves as the most common route of access for microorganisms into the bladder. Bladder catheters facilitate bacteriuria by two ways: either through direct inoculation of the bladder during catheter insertion or through biofilm ascension along the catheter. MDR-UTI has a very vague definition. According to Magiorakos et al (11) a bacterial isolate was considered non-susceptible to an antimicrobial agent when it tested resistant, intermediate or non-susceptible when using clinical breakpoints as interpretive criteria, and not epidemiological cutoffs provided by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), the Clinical and Laboratory Standards Institute (CLSI). In literal terms, MDR means resistant to more than one antimicrobial agent', but no standardized definitions for MDR have been agreed upon yet by the medical community. Many definitions are being used to characterize patterns of multidrug resistance in Gram-positive and Gram-negative organisms. For these germs, the definition most frequently used is resistant to three or more antimicrobial classes'. Another method used to characterize bacteria as MDR, is when they are resistant to one key antimicrobial agent, carbapenems for Klebsiella spp. Prior antibiotic use can be associated with a high prevalence of resistance in patients with UTI. After analyzing more than 5,000 urine culture, Bidell et al (2) noticed that more than two prior antibiotic exposures were associated with slightly higher incidences of fluoroquinolone nonsusceptibility, multidrug resistance, and extended-spectrum β-lactamase phenotype compared with no or one exposure. The authors suggest an increased risk for resistant Gram-negative pathogens among hospital patients with UTI occurring 3 days after admission. Micek et al (12) re- 370

Multidrug resistant urinary tract infection is Klebsiella spp the first enemy to fight with? vealed that exposure to antimicrobial agents in the previous 90 days is associated with significantly higher hospital mortality, longer hospital stays and higher hospital costs. The authors concluded that clinicians and hospital administrators should consider the potential impact of recent antibiotic exposure when formulating empiric treatment decisions for patients with severe infections attributed to Gram-negative bacteria. In our study, almost one quarter of patients (24.70%) had a history of antibiotic use within the last three months. Fluoroquinolones, especially ciprofloxacin were the antibiotics most frequently used prior to admission. This has leaded to a high incidence of fluoroquinolone nonsusceptibility in patients with Klebsiella spp UTI, ranging from 94.11% (levofloxacin) to almost 86% (ciprofloxacin and norfloxacin). The European Association of Urology (13) recommends routine daily personal hygiene to maintain meatal hygiene, meaning soap and water is sufficient to achieve this goal. Special attention must be given to educating non-circumcised patients to clean underneath their foreskin daily to remove smegma, as this may increase their risk of developing a UTI. Surprisingly, almost one third of patients had no access to running water and had no indoor toilets. This situation makes them have a poor hand and genitalia hygiene. It becomes difficult for many of our patient which have urinary catheter, to follow Septimus et al. (14) recommendations for a good hand hygiene before and after catheter insertion or bag manipulation to prevent device-related healthcare-associated infections. The rise in antibiotic resistance of Klebsiella spp. represents a growing threat to patients worldwide, especially when we should treat infections with carbapenemresistant Klebsiella spp. (CRKP). The treatment of these infections is problematic, as few therapeutic options are available. In a review by Tansarli et al. (15) the antimicrobial susceptibility of Klebsiella spp isolates in CAUTI varied at the following rates: amoxicillin-clavulanic acid, 0 to 69%; cefotaxime, 43 to 100%; ceftazidime, 40 to 100%; imipenem, 100%; ciprofloxacin, 53 to 100%; nalidixic acid, 51 to 94%; gentamicin, 60 to 100%; amikacin, 100%; trimethoprim-sulfamethoxazole, 0 to 56%; nitrofurantoin, 40 to 78%; tetracycline, 43 to 69%; and fosfomycin, 100%(15). In one of the few Klebsiella spp. UTI in hospitalized patients by Ben Haj et. al. 16) the susceptibility of all Klebsiella spp. isolates to the tested antibiotics was the following: amoxicillin-clavulanic acid, 60%; cefotaxime, 66%; nalidixic acid, 48%; ofloxacin, 73%; ciprofloxacin, 74%; gentamicin, 69%; tobramycin, 70%; amikacin, 97%; trimethoprim-sulfamethoxazole, 57%; nitrofurantoin, 68%; and fosfomycin, 77%. In our patients Klebsiella spp. had a high rate of resistance to ampicillin +/- clavulanic acid (>90%), cephalosporins (88-98%) excepting cefixime (35%) or vancomycin (95%). We also encountered high rates of resistance to trimethoprim-sulfamethoxazole (90%) and fluoroquinolones (85-94%), often used as first line of treatment for uncomplicated UTI and gentamicin (80%). For these antibiotics, our results are very like those obtained by El Bouamria et al. (17) in a three-year study of 321 Klebsiella spp. positive urine cultures. The trend of Klebsiella spp. incidence in our geographical area seems to be constant. In a report by Pricop et al. (18) between January 2013 and July 2014 the incidence of Klebsiella spp. UTI was of 46.15%. It had the same spectrum of re- 371

D. Puia et al. sistance throughout the study period: resistant to ampicillin, amoxicillin + clavulanic acid, cephalosporins (cefuroxime, cefotaxime, ceftazidime, cefepime), gentamicin, fluoroquinolones (norfloxacin, ciprofloxacin). Klebsiella spp MDR-UTI was associated with the insertion and replacement of JJ stents (33.33%), endourological interventions (transurethral resection of prostate - TUR-P 14.10%, transurethral resection of a bladder tumor - TUR-BT 23.08%), diabetes mellitus (19.23%), bladder tumors (17.95%) or prostatic neoplasm (14.10%), status of urethrovesical catheter carrier (46.15%) and with the insertion of probes for percutaneous nephrostomy (15.38%)(18). The inappropriate antibiotic use in Romania is a major problem. Medicine consumption in Romania, especially antibiotics, is one of the highest across the European Union. In a survey conducted by the European Commission in 2015 Romanians consumes 70% more antibiotics than the average Europeans (19,20). Every day 3.3% of Romania s population takes antibiotics. Moreover, 70% of Romanians believe antibiotics kill viruses, as compared to 49% of the Europeans in a similar case; also, 55% of Romanians believe antibiotics are efficient in flu and cold, as compared to 41% of Europeans. A similar problem is encountered in Romanians hospitals. Tarcea et al. (21) evaluated the use of restricted antibiotics in an academic hospital in Romania. The authors found that the most commonly prescribed antibiotics were vancomycin, imipenem and meropenem, but they were used inappropriately in 49.71, 46.55 and 44.06 % of the cases. CONCLUSIONS Our study revealed that in our geographical area the hospitalized patient with Klebsiella spp. MDR-UTI is often an elderly man with a history of pelvic cancer or urinary retention due to BPH which required the use of a urinary stent, frequently a bladder catheter, sometimes with poor hygiene condition for which the usually used antibiotics are not effective. Our study stresses the need for frequent re-evaluation of the prevalence of pathogens and antibiotic resistance and the adjustment of the empirical first-line treatment. Our study revealed that in our geographical area the hospitalized patient with Klebsiella spp. MDR-UTI is often an elderly man with a history of pelvic cancer or urinary retention due to BPH which required the use of a urinary stent, frequently a bladder catheter, sometimes with poor hygiene condition for which the usually used antibiotics are not effective. Our study stresses the need for frequent re-evaluation of the prevalence of pathogens and antibiotic resistance and the adjustment of the empirical first-line treatment. 372 REFERENCES 1. Sewify M, Nair S, Warsame S, et al. Prevalence of Urinary Tract Infection and Antimicrobial Susceptibility among Diabetic Patients with Controlled and Uncontrolled Glycemia in Kuwait. J Diab Res 2016; 2016: 6573215. 2. Bidell MR, Opraseuth MP, Yoon M, Mohr J, Lodise TP. Effect of prior receipt of antibiotics on the pathogen distribution and antibiotic resistance profile of key Gram-negative pathogens among patients with hospital-onset urinary tract infections. BMC Infect Dis. 2017; 17: 176.

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