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Postgraduate Medicine ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: An update on the management of urinary tract infections in the era of antimicrobial resistance Mazen S Bader, Mark Loeb & Annie A Brooks To cite this article: Mazen S Bader, Mark Loeb & Annie A Brooks (2016): An update on the management
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  Full Terms & Conditions of access and use can be found at Download by:  [Cornell University Library] Date:  22 October 2016, At: 11:33 Postgraduate Medicine ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: An update on the management of urinary tractinfections in the era of antimicrobial resistance Mazen S Bader, Mark Loeb & Annie A Brooks To cite this article:  Mazen S Bader, Mark Loeb & Annie A Brooks (2016): An update on themanagement of urinary tract infections in the era of antimicrobial resistance, PostgraduateMedicine, DOI: 10.1080/00325481.2017.1246055 To link to this article: Accepted author version posted online: 07Oct 2016.Published online: 21 Oct 2016.Submit your article to this journal Article views: 62View related articles View Crossmark data  CLINICAL FEATUREREVIEW An update on the management of urinary tract infections in the era of antimicrobialresistance Mazen S Bader a , Mark Loeb b and Annie A Brooks c a Department of Medicine, Juravinski Hospital and Cancer Centre, Hamilton, Ontario, Canada;  b Departments of Pathology & Molecular Medicine andClinical Epidemiology & Biostatistics, McMaster University Michael G DeGroote School of Medicine, Hamilton, Ontario, Canada;  c Department of Pharmacy, Hamilton Health Sciences, Juravinski hospital and Cancer Centre, Hamilton, Ontario, Canada ABSTRACT Urinary tract infections (UTIs) caused by antibiotic-resistant Gram-negative bacteria are a growingconcern due to limited therapeutic options. Gram-negative bacteria, specifically  Enterobacteriaceae ,are common causes of both community-acquired and hospital acquired UTIs. These organisms canacquire genes that encode for multiple antibiotic resistance mechanisms, including extended-spectrum-lactamases (ESBLs), AmpC-  β  -lactamase, and carbapenemases. The assessment of suspected UTIincludes identification of characteristic symptoms or signs, urinalysis, dipstick or microscopic tests,and urine culture if indicated. UTIs are categorized according to location (upper versus lower urinarytract) and severity (uncomplicated versus complicated). Increasing rates of antibiotic resistance neces-sitate judicious use of antibiotics through the application of antimicrobial stewardship principles.Knowledge of the common causative pathogens of UTIs including local susceptibility patterns areessential in determining appropriate empiric therapy. The recommended first-line empiric therapiesfor acute uncomplicated bacterial cystitis in otherwise healthy adult nonpregnant females is a 5-daycourse of nitrofurantion or a 3-g single dose of fosfomycin tromethamine. Second-line options includefluoroquinolones and  β -lactams, such as amoxicillin-clavulanate. Current treatment options for UTIs dueto AmpC-  β  -lactamase-producing organisms include fosfomycin, nitrofurantion, fluoroquinolones,cefepime, piperacillin – tazobactam and carbapenems. In addition, treatment options for UTIs due toESBLs – producing  Enterobacteriaceae  include nitrofurantion, fosfomycin, fluoroquinolones, cefoxitin,piperacillin-tazobactam, carbapenems, ceftazidime-avibactam, ceftolozane-tazobactam, and aminogly-cosides. Based on identification and susceptibility results, alternatives to carbapenems may be used totreat mild-moderate UTIs caused by ESBL-producing  Enterobacteriaceae . Ceftazidime-avibactam, colistin,polymixin B, fosfomycin, aztreonam, aminoglycosides, and tigecycline are treatment options for UTIscaused by carbapenem-resistant  Enterobacteriaceae  (CRE). Treatment options for UTIs caused by multi-drug resistant (MDR)- Pseudomonas  spp. include fluoroquinolones, ceftazidime, cefepime, piperacillin-tazobactam, carbapenems, aminoglycosides, colistin, ceftazidime-avibactam, and ceftolozane-tazobac-tam. The use of fluoroquinolones for empiric treatment of UTIs should be restricted due to increasedrates of resistance. Aminoglycosides, colistin, and tigecycline are considered alternatives in the settingof MDR Gram-negative infections in patients with limited therapeutic options. ARTICLE HISTORY Received 10 July 2016Accepted 5 October 2016Published online21 October 2016 KEYWORDS Antibiotic resistance; cystitis; Enterobacteriaceae ;Gram-negative bacteria;pyelonephritis; urinary tractinfections Introduction Urinary tract infections (UTIs) are among the most commonbacterial infections managed by clinicians [1]. UTIs exert aconsiderable impact on economic and public health resourcesand substantially affect the quality of life of those afflictedwith recurrent infections [2]. It is estimated that 0.7% of ambulatory visits are attributed to UTIs, and each year 7million ambulatory care visits by females are due to UTIs[3,4]. UTIs are the fourth most common health care-associated infection with a prevalence of 12.9%, and two-thirds are cathe-ter associated [5]. The clinical spectrums of UTIs include urethritis, cystitis,prostatitis, and pyelonephritis [6]. UTIs can also be stratifiedas either community-associated UTI (CAUTI) or health care-associated UTI (HAUTI), which include community-onsethealth care-associated infections. Health care-acquired UTIsrepresent 40% of all hospital-acquired UTIs [1].Gram-negative bacteria, specifically  Enterobacteriaceae , arecommon causes of both CAUTI and HAUTI [1]. Antibiotic resis-tance among causative Gram-negative bacilli is increasing andconsidered to be a challenge for clinicians since there arelimited treatment options. Common examples of these organ-isms include AmpC  β -lactamase- and extended-spectrum  β -lactamases (ESBLs)-producing  Enterobacteriaceae , carbape-nem-resistant  Enterobacteriaceae  (CRE), and multidrug-resis-tant (MDR)  Pseudomonas aeruginosa  [7,8]. Management of UTIs in the era of antimicrobial resistancerequires a systematic approach to diagnose the type of infec-tion and to select the optimal dose, route, and duration of the CONTACT  Mazen S Bader Juravinski Hospital and Cancer Centre, Department of Medicine, 711 Concession Street, Hamilton, OntarioL8V1C3, Canada POSTGRADUATE MEDICINE, 2017 © 2016 Informa UK Limited, trading as Taylor & Francis Group  antibiotic regimen. Unfortunately, standardized evidence-basedclinical management is often lacking in general practice [9].When approaching a patient with a suspected UTI, consid-eration should be given to the following essential elements. Does the patient have a UTI? Patients suspected of having UTIs should be initially evaluatedthrough history taking and physical examination to assesssigns or symptoms consistent with symptomatic UTI and toguide the selection of adjunct diagnostic and therapeuticstrategies. Classic symptoms and signs of UTIs include fever,acute dysuria, urinary urgency or frequency, hematuria, back pain, suprapubic tenderness, or costovertebral angle pain ortenderness. Laboratory tests confirming the diagnosis includebacteriuria ( ≥ 100,000 CFU [colony forming unit]/ml) andpyuria ( ≥ 10 WBC/hpf [white blood cells per high powerfield]) [6,10,11]. Patients with uncomplicated cystitis usually require dipstick urinalysis (UA) to support the diagnosis of UTIs. Conversely, the combination of dysuria and frequencyor urgency without vaginal discharge or irritation increases thelikelihood of acute uncomplicated cystitis to >90% in females. Therefore, these patients should be treated empirically with-out further testing [12].Urinary dipstick, used to detect the presence of leukocyteesterase and nitrite, exhibits variable test characteristicsdepending on the population studied and clinical presenta-tion. This test has a high negative predictive value (90 – 100%)in various patient populations including the elderly. Therefore,a negative urinary dipstick for leukocyte esterase and nitritesuggests that further evaluation for UTI is unnecessary, parti-cularly if the pretest probability of UTIs is low [13]. However,despite the excellent negative predictive value, a positiveurinary dipstick or UA result is nonspecific with subsequentlow positive predictive values [13]. Asymptomatic pyuria andasymptomatic bacteriuria are highly prevalent (25 – 50%) inelderly patients, particularly in female residents of long-termcare facilities (LTCFs) and patients with indwelling urinarycatheters [10,13,14]. Asymptomatic pyuria or bacteriuria in the setting of nonspecific symptoms (e.g. fatigue, malaise,worsening urinary frequency or urgency, incontinence, dizzi-ness, and confusion) is a trigger for the inappropriate use of diagnostic tests such as urine culture and inappropriate anti-biotic use among elderly, commonly in residents of LTCFs[15,16]. Vaginitis, sexually transmitted diseases (STDs), and pelvicinflammatory disease can mimic symptoms of UTIs. In fact, arecent study showed that approximately one-third of cases of STDs was misdiagnosed as UTIs [17]. What type of UTI does the patient have? UTIs can be classified according to the specific site of infectionand are often differentiated into upper and lower UTIs. Theseinclude urethritis, cystitis, prostatitis (lower UTIs), and pyelone-phritis (upper UTIs) [6,18]. Clinical presentation helps differ- entiate between upper and lower UTIs. Fever in UTIs usuallyrepresents the presence of tissue invasion and inflammationsuch as pyelonephritis or prostatitis although it may occurwith lower UTIs [6]. Urine culture is not indicated in patientswith uncomplicated cystitis since it is not associated withimproved outcomes such symptom scores [19]. However,urine cultures are indicated in patients with complicated UTIs(cUTIs), recurrent UTIs, acute pyelonephritis, or in those at risk of infection with antibiotic-resistant organisms [6,10,11]. Blood cultures do not contribute to the improved management of acute pyelonephritis without obtaining an appropriate urinesample [20]. Does the patient have complicated or uncomplicatedUTI? UTIs are usually classified as either complicated or uncompli-cated infections, irrespective of the location and severity of the infection [18]. An uncomplicated lower UTI is usuallydefined as acute cystitis occurring in a healthy, premenopau-sal, nonpregnant female with no known structural urologicalabnormalities [6]. cUTIs are associated with an underlyingcondition that increases the risk of recurrent infections ortreatment failure due to functional or anatomic abnormalitiesof the urinary tract ( Table 1). cUTIs have a greater risk of morbidity and mortality when compared with uncomplicatedUTIs [18].It is imperative to determine the severity of infection sinceuncomplicated UTIs usually require fewer diagnostic tests andcan be treated with narrow-spectrum antimicrobial agents forshorter durations. On the other hand, all patients with cUTIsrequire urine culture in order to identify the causative patho-gen due to the wide diversity of potential pathogens and risk of antimicrobial resistance.  Escherichia coli, Klebsiella pneumo-niae, Enterococcus faecalis, Enterobacter spp., Proteus mirabilis,Serratia marcescens , and  P  .  aeruginosa  are common causativepathogens in the setting of cUTIs with an increase in relativefrequency of non- E. coli   pathogens. Recurrent infection, instru-mentation, and repeat courses of antimicrobial therapyincrease the risk of antibiotic-resistant organisms causingcUTIs. [6,20]. Due to a low yield, routine blood cultures are not recom-mended for all patients with cUTIs but in pyelonephritis [20]. What is the severity of UTI in this patient?  The clinical spectrum of UTIs can range from uncomplicatedcystitis to septic shock due to severe pyelonephritis. It is Table 1.  Factors associated with complicated urinary tract infections.PregnancyDiabetes mellitusRenal failureImmunocompromised conditionsKidney transplantationInfection with antibiotic-resistant pathogensHospital-acquired infectionSymptoms persisting  ≥ 7 days prior to seeking medical careUrinary tract obstruction (benign prostatic hypertrophy, stenosis, stone,tumor, and hematoma)Indwelling urethral catheter, stent, nephrostomy tube, or urinary diversionFunctional or anatomic abnormality of the urinary tract (e.g. neurogenicbladder)Recent urinary tract instrumentation 2 M. S. BADER ET AL.  essential to determine the severity of the infection in order toguide the choice and route of empiric antibiotic therapy anddetermine whether hospital admission is warranted. Severeinfections usually require treatment with broad-spectrumintravenous empiric antibiotic therapy. Risk factors for severeUTIs include urinary tract obstruction, hydronephrosis, muco-sal trauma from indwelling catheters or urologic surgery in thepresence of bacteriuria, prolonged urologic surgery, infectionwith certain antibiotic-resistant organism, hospital-acquiredinfection, and liver cirrhosis [21 – 24]. Does the patient have risk factors for UTI withantibiotic-resistant organisms? Gram-negative bacteria, specifically  Enterobacteriaceae , canacquire genes to encode for multiple antibiotic resistancemechanisms, such as AmpC  β -lactamase, ESBLs, and carbape-nemases [25]. Increasing resistance in causative Gram-negativebacilli complicates selection of empirical antimicrobial agent.Antimicrobial resistance is associated with inappropriateempiric antibiotic therapy that can lead to poor clinical out-comes including treatment failure, development of bactere-mia, requirement for intravenous therapy, hospitalization, andextended length of hospital stay [26 – 28].Risk factors of UTIs due to antibiotic-resistant Gram-nega-tive organisms include age older than 60 years, prior UTIhistory, cUTIs, presence of a urinary catheter, chronic medicalconditions, recent hospitalizations or antibiotic treatment, andrecent travel [1,2,7,20]. E. coli   is the most common organism isolated for CAUTI andamong the most common causes of HAUTI [1,20,29,30]. There was a substantial increase in  E. coli   resistance to commonlyused antibiotics for the treatment of UTIs such as ciprofloxacin(3.6 – 11.8%) and trimethoprim – sulfamethoxazole (TMP/SMX)(17.2 – 22.2%) among outpatient females with UTIs in the per-iod of 2003 – 2012 [29]. Furthermore, the resistance rate of   E.coli   to ampicillin and cefazolin is high, approximately 40% inthis population [29,31]. AmpC  β -lactamase is encoded by genes that are commonlychromosomally mediated in bacteria (such as  Enterobacter cloacae ) but can be mobilized by plasmids to other bacteria.AmpC  β -lactamase-producing  Enterobacteriaceae  typicallyconfer clinically relevant resistance to all penicillins, cephalos-porins, and cephamycins and are not effectively inhibited byclavulanate or tazobactam [32]. The exact prevalence of UTIsdue to AmpC  β -lactamase-producing  Enterobacteriaceae  isuncertain. Among the 323 non-ESBL-producing Enterobacteriaceae  identified in community-onset UTIs in Taiwan, 50 isolates were phenotypically positive for AmpC.  E  . coli   was the most commonly isolated AmpC-producing organ-ism (60%), followed by  K  .  pneumoniae  (8%),  E  .  cloacae  (6%),and  P  .  mirabilis  (6%) [33]. Canadian studies demonstrated that 1.8 – 2.5% of urine isolates of   E. coli   were AmpC producers[34,35], and risk factors include prior use of fluoroquinolones and cephamycin [33]. Treatment options for UTIs due to AmpC  β -lactamase-pro-ducing  Enterobacteriaceae  include nitrofurantoin or fosfomycinfor cystitis and cefepime, piperacillin – tazobactam, fluoroqui-nolones, and carbapenems for pyelonephritis [34,35]. ESBLs in Gram-negative bacteria have emerged as a majorglobal public health concern, and the rate is rapidly increasing. They are commonly encountered in nosocomial-acquiredinfections or in outbreak settings but are also prevalent inthe community, particularly in LTCFs [36 – 40]. ESBLs arereported in other Gram-negative species (e. g.  Klebsiella oxy-toca and Proteus  species) in addition to  K. pneumonia  and  E.coli  . Genes that encode for ESBLs are usually found on largeplasmids accompanied by genetic determinants of resistanceagainst multiple classes of antibiotics, such as aminoglyco-sides, sulfonamides, and fluoroquinolones [41]. Enterobacteriaceae  producing CTX-M-type ESBLs (CTX-M-14and CTX-M-15 enzymes) are linked to the dissemination of  ‘ high-risk clone ’  sequence type (ST) 131. The H30 and H30Rxsubclones account for most ST131 isolates and for the associa-tion of ST131 with fluoroquinolones resistance and ESBLsproduction [36,42,43]. The prevalence of ESBLs among patho- gens causing UTIs varies according to region, the patientpopulation, and risk factors. ESBL production was detected in8.5% and 8.8% of   E  .  coli   and  K  .  pneumoniae  in North Americaand in 17.6% and 38.9% in Europe, respectively [36]. Risk factors for UTI caused by ESBL-producing organisms includehospital-acquired infection, LTCF residence, diabetes, recur-rent UTIs, and comorbidities [44]. Patients with infection dueto ESBL-producing organisms are more likely to receive inap-propriate antibiotics to experience longer hospital stays and topresent with severe sepsis and septic shock [24,27]. Fosfomycin trometamol, nitrofurantoin, and pivmecillinamare active against more than 90% of urinary isolates of ESBL-producing organisms and are considered choices for the oraltreatment of lower UTIs ( Table 2) [45 – 49]. Treatment optionsfor pyelonephritis caused by ESBL-producing organismsinclude carbapenems, ceftazidime – avibactam, fosfomycin(intravenous), cefoxitin, cefepime, temocillin, piperacillin – tazo-bactam, ceftolozane – tazobactam, and aminoglycosides[45,50 – 52].Carbapenemases, such as  K. pneumoniae  carbapenemase(KPC), Verona integron-encoded metallo- β -lactamase (VIM),New Delhi metallo- β -lactamase (NDM), and oxacillin-hydrolyz-ing (OXA)-48 types, are enzymes that neutralize carbapenemsin addition to penicillins and cephalosporins. KPC, most com-mon in the USA, and NDM-1 are the most clinically relevantenzymes in this class [53]. These enzymes are encountered in Enterobacteriaceae  species, particularly  K. pneumonia  and  E.coli,  and less frequently in other Gram-negative organismssuch as  P. aeruginosa, Acinetobacter baumannii  , and  S. marces-cens  [54]. CRE are often resistant to all  β -lactam agents andfrequently exhibit various resistance mechanisms such asAmpCs and ESBLs including genes conferring resistance tomultiple antimicrobial classes, further limiting treatmentoptions [54]. Although CRE infections are relatively infrequentworldwide, they are more common in the United States sinceemerging [53]. In a recent study, the incidence of CRE was 2.93per 100,000 population in the US where most CRE cases wereisolated from a urinary source [55]. Rate varies from region toregion, and it is estimated to be 1.8 – 2.4% based on the US,European, and Latin American data as reported in the SENTRYstudy [56]. Risk factors for infection with CRE include prior POSTGRADUATE MEDICINE 3
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