Urinary Tract Infection (UTI): Causes and Treatment

Urinary tract is the most common organ to experience infection which occurs from neonates to geriatrics. It account for 8.3 million doctor visit each year and represent the second most common infection in the human body (Sumaira Zareef et al.,2009). By the advancement of age, the attack of UTI increases in men due to prostate enlargement and neurogenic bladder. Recurrent infections are common and will lead to irreversible damage of the kidneys, which result in renal hypertension and renal failure in severe cases. In community, women are more prone to develop UTI and 20% of women experience a single episode of UTI during their lifetime and 3% of women may have more than one episode of UTI per year. Pregnancy also makes them more sensitive to infection. Catheter-associated UTI is a trenchant problem and bacteriuria is found in 5% of catheterised patients (Das R N et al., 2006). Urinary tract infection refers to the presence of microbes in the urinary tract. The frequency of pathogens varies upon hospitalization, sexual intercourse, and catheterization (Getenet B et al., 2011). About 150 million people are diagnosed for having urinary tract infection with a very high risk of morbidity and mortality (Raza S et al., 2011).

Urinary tract infection is found more in women when compared with men the reason may be due to anatomical structure or because of the urothelial mucosa attachment to the muco polysaccharide lining or due to other factors (Tampekar et al., 2006). Urinary tract infection is second only to respiratory tract in acquiring microbial infections (Raza S et al., 2011).

Classification of Urinary Tract Infection:

Urinary tract infection may be classified as upper urinary tract infection and lower urinary tract infection. According to the infected site, if its bladder then its called cystitis, if the bacterium is in the kidney then its called pyelonephrites, if its in urine the term bacteriuria is used (Getenet B et al., 2011). Manifestation of genitourinary tract infection vary from mild symptomatic cystitis to pyelonephrites and finally to septicaemia. Pyelonephrites are the sequelae of untreated or inadequately treated lower UTI and the most common cause of hospital admission during pregnancy and which lead to preterm labour(Jamie et al .,2002). Urinary tract infections are further divided into complicated and uncomplicated infections. Uncomplicated infections are those with no prior instrumentations and complicated infections are those that have done instrumentations such as indwelling, urethral catheters and it include structural and functional abnormalities (Getnet B et al., 2011). Again UTI is classified as community acquired and hospital acquired (nosocomial). In community acquired UTI single species of bacteria is found and the organisms are Escherichia coli, P.mirabilis, Pseudomonas. Hospital acquired UTI is often due to multi drug resistant strain in this similar organism but greater preponderance of Streptococci or Klebsiella is seen (Sujit K Chaudhuri., 2001).

Defnition of the precise terms in Urinary Tract Infection:

Significant bacteriuria

It is defined as the presence of 100000 bacteria per mL of urine.

Asymptomatic bacteriuria

It is defined as significant bacteriuria in infected patients with the absence of symptoms

Cystitis

It is defined as a syndrome of frequency, dysuria, urgency in which the infection is limited to bladder and urethra.

Urethral syndrome

In Urethral syndrome a conventional pathogen is present and its a syndrome of dysuria, frequency in the absence of significant bacteriuria.

Acute pyelonephrites

It is an acute infection in one or both the kidneys.

Chronic pyelonephrites

It may be due to the continuous excretion of bacteria from kidney or the recurring infection of the renal cell or due to a specific pathology of both kidneys.

Relapse and reinfection

Relapse is defined has the recurrence of infection by the same organism which intiated original infection. Reinfection is defined as the recurrence of infection by a new organism (Roger walker et al., 2003).

Several studies have demonstrated geographical variability of Pathogens occurrence among UTI inpatient and outpatient is limited by the predominance of gram negative organisms. The most frequent pathogen isolated is Escherichia coli which accounts for about 50% to 90% of all uncomplicated infections (Tampekar et al., 2006). In complicated urinary tract infection and hospitalized patients, organisms such as Enterococcus faecalis and highly resistant gram negative rods including Pseudomonas are most common (Getenet B et al., 2011).

Aetiology and microbiology:

The most common causative organism of uncomplicated UTI is Escherichia coli accounting more than 85% cases, followed by staphylococcus saprophyticus (coagulase-negative staphylococcus) accounting to nearly 15%.

The pathogens in complicated UTI or nosocomical infections are Escherichia coli accounting 50%, Proteus, Klebsiella pneumoniae, Enterobacter, Pseudomonas aeruginosa, Staphylococci and Enterococci (Barbara et al., 2008).

A very rare cause of urinary tract infection includes anaerobic bacteria and fungi and sometimes viruses which are detected by culture and nucleic acid amplification method.

Abnormalities of the urinary tract such congenital anomalies of ureter, renal stones, enlargement of prostrate in men are other causes for urinary tract infection (Roger walker et al., 2003).

Pathophysiology of UTI: (Barbara et al., 2008)

The urinary tract includes two pairs of kidneys, ureter, bladder and urethra. Urinary tract infection are defined as infections at any level of the urinary tract which include,

Upper urinary tract infection (Pyelonephrites)

Lower urinary tract infection ( Cystitis, Urethritis)

Combination of above two

The bacteria causing UTIs originate from bowel flora of the host. It can be acquired via three possible routes

1. Ascending
2. Haematogenous
3. Lymphatic pathways

In females the short length of the urethra and proximity to the perirectal area lead to the colonization of bacteria. The organisms enter the bladder from urethra and multiply and can ascend the ureters and ascend to the kidneys.

Factors that determine the development of urinary tract infections are

• The size of the inoculums
• Virulence of the microorganisms
• Competency of the natural host defense mechanisms.

Important virulence factors of bacteria are their ability to adhere to urinary epithelial cells by fimbriae. Others include haemolysin, a cytotoxic protein produced by bacteria which lyses a large range of cells including erythrocytes, monocytes, and polymorph nuclear leukocytes.

Clinical presentation:

• Pain or burning when you using bathroom
• Fever, tiredness or shakiness
• An urge to use the bathroom often and often
• Pressure in the lower belly
• Urine that smells bad and looks cloudy or reddish
• Nausea or back pain

Lower urinary tract infection – Dysuria, urgency, nocturia, Increased frequency of urination

Upper urinary tract infection – Fever, flank pain, vomiting malaise.

Clinical investigation: (Roger walker et al., 2003)

Laboratory diagnosis is successful when an uncontaminated urine sample is obtained for microscopy and culture. The respective patients need to instruct to produce mid stream urine sample (MSU) and then its collected into a sterile aliquot and then transferred into the specimen pot and finally is submitted to the laboratory.

Dipsticks

It is a rapid testing for urinary blood, nitrites, proteins and leukocyte esterase. The colour changes are assessed.

Microscopy

It is the first step in the diagnosis of urinary tract infections. Urine is placed on a slide and then covered with a cover slip and is examined under lens 40x.

Culture

The patients urine is streaked in agar medium and is incubated for 24 hours at 370C and identify the single bacterial species which as initiated the particular infection.

Treatment of UTI:

Non specific treatment

Urinary tract infected patients are advised to drink a lot of fluids, this practice is on the basis that the bacteria is removed by frequent bladder emptying. Urinary analgesics such sodium citrate which will alkanize urine is used with antibiotics as an adjunct therapy (Roger walker et al., 2003).

Pharmacological treatment of UTI

Antibiotics are commonly used in Urinary tract infections. The modes of action of antibiotics may be,

1. Inhibition of Bacterial Cell Wall Synthesis
2. Inhibition of Cytoplasmic Membrane Function
3. Inhibition of Nucleic Acid Synthesis
4. Inhibition of Protein Synthesis
5. Control of Microbial Enzymes
6. Substrate Competition with an Essential Metabolite (Barar F. S. K., 2007)

UTI are mainly treated with broad spectrum Cephalosporins, Fluroquinolones, and Aminoglycosides. Cephalosporins are cell wall inhibitors which are commonly used for treating urinary tract infections caused by Gram negative organisms. It include Cefotaxime, Cephradine, Ceftazidime etc. Flouroquinolones act by inhibiting the activity of DNA gyrase and topo isomerase which are the enzymes needed for bacterial DNA replication and it includes Ciprofloxacin, Ofloxacin, Enoxacin. Aminoglycoside act by inhibiting bacterial protein synthesis it include Gentamycin, Kanamycin, Amikacin etc (Farhat Ullah et al., 2009).

Oral therapy in urinary tract infection is Sulphonamides example (TMP-SMX) PenicillinS which include Ampicillin, Amoxicillin- clavulanic acid. Cephalosporins example Cephalexin, Cephadrine. Tetracyclines example Doxycycline, Minocycline. Fluroquinolones example Levofloxacin, Nitrofurantine. Parentral therapy is done with Carbapenems example Imipenem-Cilastatin. Aminglycosides example Amikacin, Gentamycin (Barbara et al., 2008).

2.9 Treatments of infections of urinary tract:

(S.D Seth et al., 1999)

Treatment of Lower Urinary Tract Infections

Single-dose Trimethoprim -Sulphamethoxazole (400mg+2g) are used to treat acute uncomplicated episode of cystitis.

Acute urethritis can be treated with Doxycycline 100 mg twice a day for 7 days.

Single dose therapy must be restricted in patients where symptoms are present for less than 10 days. In more complicated cases seven days therapy with antibiotics should be given and alternatively broader spectrum antibiotics are used.

Treatment of upper Urinary Tract Infections

10-14 day course of Trimethoprim-Sulphamethoxazole, Trimethoprim in a single dose, Cephalosporins, or Aminoglycoside gives adequate therapy. If recurrence occurs then the patient should be investigated for calculi and other urologic disease.

Treatment of Urinary Tract Infections during Pregnancy

Acute cystitis during pregnancy is treated with Amoxicillin, Nitrofurantoin,or Cephalosporin for 4 days.

Acute pyelonephtites is managed generally with Cephalosporin or extended spectrum Penicillin.

Treatment for Recurrent Urinary Tract Infections

In this a drug capable of achieving high tissue concentration is needed.7-14 days high treatment is given.

Treatment of Asymptomatic Infections

Asymptomatic bacteriuria is confirmed by a minimum of two positive cultures. An oral therapy for 1 week with the most sensitive agent is given primarly.

Treatment for Catheter Associated Urinary Tract Infection

Asymptomatic bacteriuria in catheterized patients is not treated if they are not at a high risk of sepsis.

Treatment for Prostatitis

The pathogen found in this is mainly Gram Negative Bacilli. Trimethoprim- Sulphamethoxazole, Erythromycin, Ciprofloxacin can penetrate prosthetic tissue and are mostly effective. If Cocci are found cloxacillin may be given.

Chemoprophylaxis of Urinary Tract Infections

It is indicated to patients with a very frequent symptomatic infection. A single dose Trimethoprim-Sulphamethoxazole (80mg TMP+400 mg SMZ) or Nitrofurantoin (50 mg) is found to be effective.

Drug resistance: (Michelle.A.Clark et al., 2012), (Barar F.S.K 2010).

Bacteria are said to be resistant to an antibiotic if the maximal level of that antibiotic which can be tolerated by the host does not alter the bacterial growth. Bacterial resistance to antibiotics may be either Natural or Acquired.

Natural resistance

Natural resistance is genetically determined and it depends upon the absence of a metabolic process which is affected by the respective bacteria.

Acquired resistance

Acquired resistance is the resistance which is seen in a previously sensitive bacterial pathogen and it involves a very stable genetic change which is heritable from one generation to another generation. The common mechanism is by mutation, adaptation, or by the development of multiple drug resistance which is as a result of transfer of genetic material from bacteria to bacteria by transformation, transduction, or conjugation. Microbial species which are normally responsive to a particular drug may develop more virulent, resistant strains due to,

• Genetic alterations
• Spontaneous mutations of DNA
• DNA transfer of drug resistance

B) Altered expression of proteins in organism

Modification of target site

Decreased accumulation

Enzymtic Inactivation

A) Genetic alterations

Acquired antibiotic is due to the temporary or permanent alteration of organisms genetic information.

Spontaneous mutation of DNA

Chromosomal alteration occurs by insertion or substitution of one or more nucleotides within the genome. The mutation may be lethal to the cells. If the cells survive it will replicate and transmit its mutated properties to other cells.

DNA transfer of drug resistance

It occurs due to DNA transfer from one bacterium to other. Resistance gene are plasmid mediated and can be incorporated into host bacterial DNA.

B) Altered expression of proteins in organism

It occurs by variety of mechanisms, such as a lack of or alteration in target site, increased efflux of the drug or by the expression of antibiotic inactivating enzymes.

Modification of target sites

The change in the antibiotic target site through mutation can lead to resistance. Example, S pneumonia resistance to beta lactums involves alteration in one or more of major bacterial penicillin binding protein.

Decreased accumulation

If the drug is unable to attain access to the site of its action to kill the organism’s resistance confers.

Enzymic inactivation

The ability to destroy antibiotic agent by the pathogen can confer resistance. Antibiotic inactivating enzymes include

a) Beta lactamases (Hydrolytically inactivate beta lactum ring of penicillin)

b) Acetyl transferases (Transfer an acetyl group to antibiotics)

c) Esterases (Hydrolyze the lactone ring of macrolides)

Antibiotic tolerance:

The term antibiotic tolerance is used when the antibiotic merely inhibits its multiplication and growth but no longer kills the microbial pathogen. Tolerant microbial pathogen starts to grow after antibiotics are stopped.

Cross resistance:

It is defined as a phenomenon in which bacteria resistant to one drug is resistant to another drug to which the bacteria is not exposed before.

Examples are Neomycin and Kanamycin.

Prevention of drug resistance: (K.D Tripathy 2006)

Indiscriminate and prolonged use of antibiotics should be stopped it will minimise resistant strains so there will be less chance to preferentially propagate

Rapidly acting and narrow spectrum antibiotics should be preferred. Broad spectrum is used when a proper one cannot be determined

When prolonged therapy is needed use combination of Anti microbial agents

Treatment should be intensively done for the infections by organism which develops resistance Example, Staphylococcus aureus.

Evaluation of urinary tract pathogen and principles of antibiotic dosing: (Michelle.A.Clark et al., 2012), (Sharma H L et al 2011)

The traditional way for the evaluating urinary tract pathogens is urine culture and antibiotic susceptibility testing. The major drawback of current microbiological analysis is time lapse of more than a day (Vesna Ivancic et al., 2008). The five important characteristic which influence frequency of dosing of all antibiotics are,

Minimum inhibitory concentration (MIC)

It is the lowest concentration of antibiotic that inhibit bacterial growth. To have effective therapy the clinically obtainable antimicrobial concentration should be greater than MIC.

Minimum bactericidal concentration (MBC)

It is the lowest concentration of antibiotic agent that results in 99.9% decline in colony count after incubation.

Concentration dependent killing effect [CDKE]

Antibiotics are most effective when higher blood concentration is reached periodically. These bactericidal antibiotics are said to be concentration -dependent killing (CDK). In drugs whose killing action is CDK the extent and rate of killing increases with increase in drug concentration. Examples Amino glycosides, Fluroquinolones.

Time dependent killing effect [TDKE]

Antibiotics are most effective when the blood concentrations are maintained above the minimum inhibitory concentration for the maximum long duration possible. These bactericidal antibiotics exhibit time -dependent killing (TDK). In drugs whose killing action is (TDK) the activity of antibiotics continue as long as serum concentration are maintained above the minimum inhibitory concentration. Examples Vancomycin, Beta Lactums.

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Post -antibiotic effect [PAE]

A suppression of bacterial growth which is persistent after a brief exposure to antibiotics agents is said to be post-antibiotic effect. In post antibiotic effect the suppression or inhibition of bacterial growth is found even when the bacterial agent is no longer present or its concentration is very less than MIC. Examples of drugs which show significant PAE are Tetracycline, Amino glycosides.

The aetiology of UTI and the antibiotic susceptibility of uropathogens have been changing over the past decade. The extensive uses of antibiotics have invariably resulted in the development of resistance which has become major problem in recent years. Antibiotic treatment which are of shorter duration than required, and the treatment administered without considering antibiotic and organism sensitivity as resulted in more resistance in bacterial strains (Mohammed Akram et al., 2007), (Eshwarappa M et al., 2011). To find out the most effective empirical treatment, investigating the epidemiology of UTI is a fundamental approach to guide the expected interventions (Getnet B et al., 2011). Since the distribution of microbial pathogens and their susceptibility is variable regionally and it is necessary to have a knowledge of uropathogens and sensitivity in a particular setting (Muhammed Naeem et al., 2010).

The selection of antimicrobial agents require the following knowledge,

• The organism’s identity
• The organism’s susceptibility to particular agent
• The site of the infection
• Patient factors
• The safety of the agent
• The cost of therapy

However, in critically ill patients need immediate treatment i.e. the therapy is initiated soon after specimens for laboratory analysis have been obtained before the culture result and selection of drug is influenced by the site of infection and patients history or by the association of particular organism

Prevention and prophylaxis: (Roger Walker et al).

Cranberry juice:

It has been thought beneficial for the prevention of urinary tract infections. The benefit of drinking cranberry juice instead of antibiotics has reduced resistance of bacteria.

Antibiotic prophylaxis:

It is indicated to patients who are having reinfections. If the reinfection is after sexual intercourse then after intercourse a single dose of antibiotics is taken. In other cases low dose is beneficial.

Patient counselling of UTI:

Drinking plenty of clear liquids will keep urine diluted.

Good personal hygiene following urination and bowel movements. Cleaning self front to back from vagina to anus.

Urinate frequently to wash out bacteria that may be present, avoid holding urine for prolonged periods of time.

Urinate after intercourse to wash out bacteria that may have been introduced into the urethra.

Avoid wearing tight jeans, wet bathing suites.

Present scenario of UTI:

New studies reveal that the risk of urinary tract infection is high among boys who has not circumcised and had a visible urethral meatus.

Another line of UTI research has indicated that women who are “non-secretors” of certain blood group antigens may be more prone to recurrent urinary tract infections because the cells lining the vagina and urethra may allow bacteria to attach more easily.

Scientists have worked out an effective new approach to treat urinary tract infections (UTIs) by dumping antibiotics. It involves so-called FimH antagonists, which are non antibiotic compounds and would not contribute to the growing problem of pathogens resistant to antibiotics.