Multidrug resistant E. Coli in urinary tract infections. Sensitivity to Amikacin

CONTENTS

ABSTRACT

INTRODUCTION

LITERATURE REVIEW

URINARY TRACT INFECTION

DIFFERENTIAL DIAGNOSIS OF UTI

COMPLICATIONS OF UTI

PREVENTION OF UTI

E. COLI

ANTIMICROBIAL RESISTANCE

PREVENTION OF ANTIMICROBIAL RESISTANCE

MULTIDRUG RESISTANT E COLI

AMINOGLYCOSIDES

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSION

REFERENCES

ANNEXURE

ABSTRACT

Introduction:

Urinary tract infection (UTI) is the commonest bacterial infection worldwide resulting from the invasion and multiplication of bacteria in urinary tract. It is more common in females due to short urethra and close proximity with anal canal. It can be mild like cystitis to severe leading to septicemia and death. Escherichia coli (E. Coli) is the leading organism responsible for UTI. Resistance to antibiotics is on rise particularly in developing countries where no antibiotic policies are made. Multidrug resistant (MDR) strains of E. coli are emerging which has made the use of many antibiotics inappropriate. Determination of MDR strains and their susceptibility to amikacin was determined in this study.

Objectives:

The main objectives were to determine the frequency of MDR strains of E. coli causing UTI and to determine their sensitivity to amikacin.

Material and methods:

Study design: Descriptive cross sectional

Study duration: From 21st August 2015 to 30th June 2016.

Setting: Department of medicine Khyber Teaching Hospital, Peshawar.

Sample size: Sample size was 179.

Results:

Out of 179 patients with positive urine culture for E. coli, infection was more common in females, 116(64.8%) were females, 63(35.2%) were male with a male to female ratio of 1:1.84, high prevalence of drug resistance, MDR strains were isolated from 155(86.6%), which showed a sensitivity of 92.25% to amikacin.

Conclusion:

Drug resistance is on rise with a trend towards prevalence of multidrug resistant strains in the community, cautious and appropriate use of antibiotics is advised.

Key words:

Urinary tract infection, E. Coli, Antibiotic sensitivity, Multi drug resistance (MDR), Amikacin.

INTRODUCTION

Urinary tract infection (UTI) refers to inflammation of the urinary tract due bacteria which invades the tract, replicate there and then cause inflammation. This multiplication may be in the urinary bladder but it may ascend to the ureter and then kidneys. From there it may spread to the whole body. So this infection may be mild in the form of cystitis but at the times it can be so severe leading to pyelonephritis, septicemia and death.17 Urinary tract infection is one of the most common bacterial infection worldwide1 as well as in Pakistan Fehler! Verweisquelle konnte nicht gefunden werden., putting a lot of economic and financial burden on the health system. Worldwide 150 million UTIs occur each year1, consuming 6 billion dollars in health system globally2. Urinary tract infection is much more common in developing countries. A number of factors contribute to and play important role in the high prevalence of UTIs in females as compared to males. These factors responsible include short urethra in females, close proximity with anal canal, drier urethral meatus and lack of prostatic secretions which has antibacterial properties3. Different organisms are responsible for causing infection in the urinary tract namely E. Coli, E. Faecalis, K. Pneumoniae, Pseudomonas, S. Aureus and proteus are the most common uropathogens4. Among them E. Coli is the leading organism responsible for urinary tract infections in 85% of community acquired and 50% of hospital acquired urinary tract infection4.

Different factors play important role in the prevalence of UTI. These include age, gender, co morbidities like diabetes mellitus (DM); human immunodeficiency virus/acquired immunodeficiency (HIV/AIDs), urethral strictures, hypospadias, immune suppressed states, steroids use, urological and gynecological interventions etc3. It is stated bacteria develop in at least 10-15 percent of hospitalized patients with indwelling urethral catheters.5 Catheter associated infections are responsible for almost 34% of health care associated life threatening infections. Prolonged catheterization, severe underlying illness, disconnection between the catheter and drainage bag and lack of antimicrobial therapy are some of the risk factors responsible for catheter associated UTI.3

Resistance to antibiotics is growing problem and cause of great clinical concern worldwide6. Risk factors involved in the development of drug resistance include over and misuse of antibiotics9,10, particularly in developing countries of the world, quackery and in appropriate use, under dosing and incomplete courses of antibiotics.9

Resistance pattern of microorganisms is not uniform and it varies with time and environment7.Bacterial agents acquire resistance through different mechanisms. This includes recombination of foreign DNA in bacterial chromosome, horizontal gene transmission and change in genetic makeup.8

E. coli is the most common organism responsible for both community and hospital acquired infection. Extended spectrum beta lactamase producing strains of E. Coli are becoming common.11Over and misuse of antibiotics, under dosing and incomplete courses of antibiotics, use of over the counter medications, use of antibiotics without the knowledge and awareness of local antibiotics sensitivity, lack of hospital policies and antibiogram all are leading to the emergence of resistant strains of E. Coli.12

Multidrug resistant strains of E. Coli has made the use of many first line antibiotics like penicillins, cephalosporin, fluoroquinolones, aminoglycosides and sulfonamides inappropriate. The development of this resistance has made it much more difficult to clear the infection and decrease the morbidity and mortality even from uncomplicated urinary tract infections.14

Antimicrobial agents are the mainstay of treatment in the urinary tract infections. Determining the prevalence of multidrug resistant strains of E Coli and their antibiotic sensitivities is of utmost importance.

Amikacin one of the aminoglycosides is the antimicrobial agent with more gram negative coverage. Sensitivity of E Coli in urinary tract infections to this drug is still retained with only 6.9% resistance documented so far.15

The situation of antibiotic resistance is worse in Pakistan compared to developed countries. Lack of standard practice, quackery, self medication, poverty,over the counter use of antibiotics, lack of national policy and surveillance and lack of local data on antibiotic resistance are the factors leading to difficult situation.

The purpose of current study conducted was to find the burden of multidrug resistant strains of E. Colicausing UTI, find out the local prevalence of MDR strains and their sensitivity to amikacin in order to provide suggestion regarding empirical therapy in urinary tract infections.

LITERATURE REVIEW

URINARY TRACT INFECTION

DEFINITION OF URINARY TRACT INFECTION

A UTI is an infection in the urinary tract. Infections are caused by microorganisms. Though bacteria are the most common cause of UTIs; it is rarely caused by viruses and fungi too. Normally, bacteria that enter the urinary tract are rapidly removed by the body’s defense mechanisms before they cause symptoms. However, sometimes bacteria overcome the body’s natural defenses and cause infection. There are different entities of UTI, it can be symptomatic or asymptomatic, complicated or uncomplicated. When infection is there without causing symptoms it is termed asymptomatic bacteriuria. It usually does not require treatment. Uncomplicated UTI refers to infection in a non pregnant, outpatient woman without anatomic abnormality or instrumentation of the urinary tract. All other types comes under the term of complicated UTI. Spectrum of urinary tract infection vary widely. A bladder infection is called cystitis and it is the most common presentation in UTI. Infection of the prostate is called prostatitis. Bacteria may travel up the ureters to multiply and infect the kidneys. A kidney infection is called pyelonephritis.25From there infection may spread to the blood converting to septicemia and may lead to death.16

EPIDEMIOLOGY OF URINARY TRACT INFECTION

Urinary tract infection is one of the most common bacterial infection worldwide, more common in developing countries and more common in females as compared to males.Annual incidence of UTI in females is about 12% and almost 1 in 3 females will have at least one episode of UTI requiring antimicrobial therapy at the age of 24 years. Almost 50 percent of females experience at least one episode of UTI during their lives.18-20 Reports of high incidence of community acquired urinary tract infections are available from Asia Pacific, Denmark, Japan, India, Russia, and the USA.21 In the USA alone, every woman visits physician at least twice for the management of UTI.22 Although in neonatal age due to congenital malformations and urinary obstruction due to prostatic hyperplasia after 50 years of age UTI is more common in males.The difference in UTI prevalence between men and women is attributed to a number of factors which include the greater length of male urethra, greater distance between anus and urethral meatus, the drier environment surrounding the male urethra and the antibacterial activity of prostatic fluid.3

RISK FACTORS FOR URINARY TRACT INFECTION23

A number of risk factors are encountered in urinary tract infection. The most important among them are

- Diabetes mellitus,
- urinary obstruction,
- functional anatomical abnormalities,
- urinary retention,
- incontinence,
- maternal history of UTI,
- first UTI at the age of 15,
- use of diaphragm,
- spermicides and sexual intercourses,
- new partners,
- Urological or gynecological instrumentation.

DM is a risk factor for a number of infections most noticeable UTI due to immunosuppressed state, hyperglycemia, immune modulation etc. spermicide use and sexual intercourse causes periurethral colonization of E. coli for prolonged periods and thus increases the chances of urinary tract infection. Maternal history of UTI and history of UTI in early life increases chances of recurrence by 2-4 times and both signify some inherited or shared environmental factors contributing to UTI. Specific risk factors for UTI in healthy men include lack of circumcision, homosexuality or intercourse with an infected female partner.

ETIOLOGY OF URINARY TRACT INFECTION

Urinary tract infection is caused by bacteria. The enteric gram negative rods are the most common organisms isolated from the urinary tract. Among them E. coli is the most common organism responsible. It is called superbug in the urinary tract infection.15 Other gram negative organisms isolated include klebsiella, morganella, proteus. Similarly gram positive organisms causing UTI include staphylococcus saprophyticus, staphylococcus aureus, streptococcus and enterococcus, citrobacter.12E. coli accounts for 75 to 90 percent of infections in the urinary tract, Klebsiella,proteus, pseudomonas, citrobacter, enterococci, staphylococcal and streptococci cause UTI with variable percentage.

PATHOGENESIS OF URINARY TRACT INFECTION24,28

The interplay of host, environmental factors and pathogen play role whether a symptomatic infection after invasion of bacteria will occur. Most uropathogens arise from the rectal flora and colonize the bladder via the periurethral area and then urethra. Anything that increases the likelihood of bacteria entering the bladder and staying there increases the chances of UTI. A small percentage of UTI is also caused by bacterial invasion through hematogenous route.

Environmental factors:

Vaginal ecology : In women, vaginal ecology is an important environmental factor affecting the risk of urinary tract infection. Alteration in the vaginalmicrobial flora and colonization of the vagina and periurethral area with organisms from the intestinal flora (usually E. coli) is the initial step in the pathogenesis of UTI. Sexual intercourse is associated with an increased risk of vaginal colonization with E. coliand thereby increases the risk of UTI. Spermicide is toxic to the normal vaginal microflora and thus is associated with an increased risk of E. colivaginal colonization and bacteriuria. In postmenopausal women, the previously predominant vaginal lactobacilli are replaced with colonizing gram-negative bacteria.

Anatomic and functional abnormalities: Any condition that permits urinary stasis or obstruction predisposes the individual to UTI. Foreign bodies such as stones or urinary catheters provide an inert surface for bacterial colonization and formation of a persistent biofilm. Thus, vesicoureteral reflux, ureteral obstruction secondary to prostatic hypertrophy, neurogenic bladder, and urinary diversion surgery create an environment favorable to UTI. In persons with such conditions, E.colistrains lacking typical urinary virulence factors are often the cause of infection. Inhibition of ureteral peristalsis and decreased ureteral tone leading to vesicoureteral reflux are important in the pathogenesis of pyelonephritis in pregnant women. Anatomic factors—specifically, the distance of the urethra from the anus—are considered to be the primary reason why UTI is predominantly an illness of young women rather than of young men.

Host factors:

The genetic background of the host influences the individual’s susceptibility to recurrent UTI, at least among women. A familial disposition to UTI and to pyelonephritis is well documented. Women with recurrent UTI are more likely to have had their first UTI before the age of 15 years and to have a maternal history of UTI. A component of the underlying pathogenesis of this familial predisposition to recurrent UTI may be persistent vaginal colonization with E . coli, even during asymptomatic periods. Vaginal and periurethral mucosal cells from women with recurrent UTI bind threefold more uropathogenic bacteria than do mucosal cells from women without recurrent infection. Epithelial cells from women who are non-secretors of certain blood group antigens may possess specific types of receptors to which E. colican bind, thereby facilitating colonization and invasion. Mutations in host response genes (e.g., those coding for Toll-like receptors and the interleukin 8 receptor) also have been linked to recurrent UTI and pyelonephritis.

Microbial factors:

An anatomically normal urinary tract presents a stronger barrier to infection than a compromised urinary tract. Thus, strains of E. colithat cause invasive symptomatic infection of the urinary tract in otherwise normal hosts often possess and express genetic virulence factors, including surface adhesins that mediate binding to specific receptors on the surface of uroepithelial cells. The best-studied adhesins are the P fimbriae, hairlike protein structures that interact with a specific receptor on renal epithelial cells. (Theletter Pdenotes the ability of these fimbriae to bind to blood group antigen P, which contains a D-galactose-D-galactose residue.) P fimbriae are important in the pathogenesis of pyelonephritis and subsequent bloodstream invasion from the kidney. Another adhesin is the type 1 pilus (fimbria), which all E. colistrains possess but not all E. colistrains express. Type1 pili are thought to play a key role in initiating E. colibladder infection; they mediate binding to uroplakins on the luminal surface of bladder uroepithelial cells. The binding of type 1 fimbriae of E. colito receptors on uroepithelial cells initiates a complex series of signaling events that leads to apoptosis and exfoliation of uroepithelial cells, with the attached E. coliorganisms carried away in the urine.

SIGNS AND SYMPTOMS OF URINARY TRACT INFECTION

Signs and symptoms usually vary depending upon the spectrum or site of the urinary tract involved. An account of different spectrums is given below:

Cystitis: 27

Symptoms associated with cystitis include

- Dysuria,
- Nocturia,
- frequency
- Urgency.
- Suprapubic pain,
- Hesitancy and sometimes hematuria is also present.

Prostatitis:

It can be acute or chronic. Signs and symptoms of acute prostatitis include

- Fever and chills,
- Perineal pain,
- Dysuria,
- Frequency and urgency.

Chronic prostatitis presents as chronic pelvic pain and recurrent episodes of cystitis.

Pyelonephritis: 27

Mild pyelonephritis can present as

- low-grade fever
- lower back or costovertebral angle pain

Severe pyelonephritis can manifest as:

- High fever with rigors,
- Nausea and vomiting,
- Flank and/or loin pain.

Symptoms are generally acute in onset, and symptoms of cystitis may not be present. Fever is the main feature distinguishing cystitis and pyelonephritis. The fever of pyelonephritis typically exhibits a high spiking picket-fence pattern and resolves over 72 h of therapy. Sometimes papillary necrosis and subsequent obstructive nephropathy can ensue in pyelonephritis, particularly in patients with diabetes mellitus. Similarly emphysematous pyelonephritis is severe pyelonephritis characterized by gas formation in the kidney and it almost exclusively occur in patients suffering from diabetes mellitus. If the infection is severe enough then it can spread to the blood and lead to Septicemia, shock and even death.

DIAGNOSIS OF URINARY TRACT INFECTION28

History and examination:

History and clinical examination play a pivotal role in diagnosing urinary tract infection. Literature evaluating the probability of diagnosing acute UTI on the basis of history and clinical examination showed that, in women presenting with at least one symptom of UTI (dysuria, frequency, hematuria, or back pain) and without complicating factors, the probability of acute cystitis or pyelonephritis is 50%.26 The even higher rates of accuracy of self-diagnosis among women with recurrent UTI probably account for the success of patient-initiated treatment of recurrent cystitis. If vaginal discharge and complicating factors are absent and risk factors for UTI are present, then the probability of UTI is close to 90%, and no laboratory evaluations needed. Similarly, a combination of dysuria and urinary frequency in the absence of vaginal discharge increases the probability of UTI to 96%.Further laboratory evaluation with dipstick testing or urine culture is not necessary in such patients before the initiation of definitive therapy.

Young males: UTI is common in young males if they are

- Having anatomic abnormalities;
- Being sexually active
- Sexually transmitted disease (STD) – related urethritis.

Elderly males: In these patients the typical manifestations of UTI may be absent or replaced by vague findings of failure to thrive or worsening mental status. In addition, failure to consider an obstructing urinary calculus in this patient population results in delay of inpatient consultation with a urologist in the septic elderly patient.

Patients with diabetes and those with recent urinary tract instrumentation, recent hospitalization, or taking broad-spectrum antibiotics have an increased incidence of resistant organisms.

Diagnostic tests

Urine culture:

Urine culture is the gold standard test for diagnosing UTI. The organism is grown on culture media. In females a colony count of > 102/ml is more sensitive and specific compared to a threshold of 105/ml. despite its importance in diagnosing infections more accurately there are a number of limitations like

- Culture results take time (at least 24 hours)
- Prior antibiotic use affect the growth
- Contamination with normal microbial flora from urethra, skin and vagina is possible.

Urine dipstick:

Dipstick is also useful test in diagnosing UTI. Dipstick test is easy to perform and detects leukocyte esterase or nitrites. Normally urine should not show any trace of nitrites. Nitrites presence in urine is an indirect clue towards the presence of nitrate reducing bacteria in the urine. The first voided urine is the accurate sample for nitrite detection by the dipstick. However a negative dipstick in the presence of strongly suggestive history does not rule out urinary tract infection.29 Enough nitrites must accumulate in the urine to reach threshold of detection. If a patient consumes more fluids and voids urine frequently then dipstick test for nitrites is less likely to be positive.28

Urinalysis:

Urine microscopy is easy test to perform to diagnose UTI but due to methodological limitations the sensitivity in detecting UTI with <105cfu/mL by gram stained microscopy is low. Some studies have found that experienced workers can achieve better diagnostic precision than with urine culture. However, the available studies on microscopy are heterogenous and all review articles conclude that it is difficult to make general statements.30

DIFFERENTIAL DIAGNOSIS OF UTI

Dysuria one of the most common symptom associated with urinary tract infection also occurs in urethritis. Determining the history of urinary and genital tract symptoms and sexual encounters, combined with laboratory testing of urine and urethral swabs, should allow differentiation of the 2 conditions. Absence of bacteruria despite symptoms of frequency, urgency, or dysuria suggests urethritis. However, bacteruria may be symptomatic or asymptomatic.

Sterile pyuria:

The differential diagnoses for infectious causes of sterile pyuria include

- perinephric abscess,
- urethral syndrome,
- chronic prostatitis,
- renal tuberculosis, and fungal
- Infections of the urinary tract, including C neoformans and Coccidioidesimmitis.
- uric acid and hypercalcemic nephropathy,
- lithium and heavy metal toxicity,
- sarcoidosis,
- interstitial cystitis,
- polycystic kidney disease,
- genitourinary malignancy, and
- Renal transplant rejection.

Prostatitis

Prostatitis can coexist with benign prostatic hyperplasia (BPH) and prostate cancer. The symptom complex of BPH and chronic prostatitis overlap; older men are sometimes misdiagnosed with one or the other. In addition, prostatitis can increase prostate-specific antigen levels, raising the concern for prostate cancer. Young men have a very low incidence of UTI; if UTI is diagnosed frequently in this population, the physician is probably overlooking the far more likely sexually transmitted disease (STD)–related urethritis/prostatitis.

Cystitis

In men older than 50 years, the presentation of cystitis is difficult to differentiate from that of obstructive presentation of prostatic hyperplasia, transitional cell carcinoma of the bladder, or acute or chronic bacterial prostatitis. In young men, urolithiasis, bladder cancer, and strictures are included in the differential diagnoses. Microscopic hematuria is quite common in patients with cystitis; when found without symptoms or pyuria, it should prompt a search for malignancy. Other factors to be considered in the differential diagnoses include

- Calculi,
- Vasculitis,
- Renal tuberculosis, and
- Glomerulonephritis.

In a developing countries, hematuria is suggestive of schistosomiasis, which can be associated with salmonellosis and squamous cell malignancies of the bladder.

Xanthogranulomatous pyelonephritis

It is a rare, but severe, renal infection that is clinically difficult to differentiate from renal tumors. It can progress to non-function and swelling of the involved kidney, and it is often associated with obstructing calculi. Proteus is the most common pathogen, followed by E coli. A granulomatous reaction with suppuration results in destruction and swelling of the renal parenchyma. Although no distinguishing characteristics can be observed upon imaging, the diagnosis can be made by examining cytologic specimens; the lipid material collects in macrophages (xanthoma cells). Pus and debris may fill the collecting system, creating the condition known as pyonephrosis.

Tuberculosis

Tuberculosis involves the prostate, but epididymitis is more commonly of male genital tuberculosis. The testis and seminal vesicles may also be involved. A palpable mass may be present in most cases. Though patients may present with infertility, tuberculosis may be spread by semen.

Differential Diagnoses

The following clinical conditions are included in the differential diagnosis of urinary tract infection

- vesicoureteric reflux
- Clamydial infections
- Chronic pelvic pain syndrome
- Benign prostatic hyperplasia
- Prostatitis
- Acute pyelonephritis
- Chronic pyelonephritis
- Septicemia
- Genitourinary tuberculosis
- Urinary tract obstruction
- Xanthogranulomatous pyelonephritis
- Appendicitis
- Urethritis
- Vaginitis
- Epididymitis
- Pelvic inflammatory disease
- Nephrolithiasis

TREATMENT OF URINARY TRACT INFECTION

Cystitis:

Treating female patients with uncomplicated cystitis brings significant symptomatic and bacteriologic improvement and better prevention of reinfection. 31 Although, treatment also selects for antibiotic resistance in uropathogens and commensal bacteria and has adverse effects on the gut and vaginal flora32 that’s why trend is changing towards good symptom control and delaying antibiotics use for 48 hours.33

Currently different therapeutic approaches are recommended for complicated and uncomplicated UTI. Following is an account of UTI management depending upon the status and site of infection.

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