Christopher Chiu1
(1)
Infectious Diseases and Microbiology, Centre for Respiratory Infection, National Heart and Lung Institute, London, UK
Christopher Chiu
Email: c.chiu@imperial.ac.uk
Abstract
Urinary tract infections (UTIs) are among the most common of all bacterial infections. They are an important cause of morbidity and mortality with a spectrum of severity that ranges from mild self-limiting infection to life-threatening systemic disease. Although they are commonly curable with antibiotics, widespread use of antimicrobials has inevitably led to a massive increase in UTIs caused by drug-resistant organisms. This has made antibiotic choice for empirical and rational treatment increasingly difficult. Here, we discuss the microbiology of UTIs, including the organisms that cause them, the interplay between bacteria and host that causes disease, mechanisms of antibiotic resistance, and factors influencing the choice of antibiotic for treatment. Through further understanding of the biology of the bacterial pathogens that cause UTIs, we aim to promote more responsible antibiotic prescribing in order to slow the pandemic spread of multiresistant organisms.
Keywords
BacteriaAntibioticsResistancePathogenesisRisk factorsESBLAmpCVRE
Definitions, Classifications, and Antibiotics
Urinary tract infection (UTI) may be defined as the presence of pathogens in the urinary tract. They are among the most common of bacterial infections and are frequent causes of morbidity and mortality. As the second most common reason for the prescription of empirical antibiotics, UTIs are also major drivers of antibiotic usage and antibiotic resistance. It is therefore essential that we understand the pathogenesis of these conditions so that they can be managed appropriately, not only for the benefit of the individual patient but also in order to control the spread of multidrug-resistant organisms.
How Common Are Urinary Tract Infections?
UTIs are extremely common, accounting for an estimated seven to ten million adult physician office visits each year in the USA [1] and 1–3 % of consultations in the UK general practice [2]. They are most frequent in infants, young women, and the elderly, with around a third of women by the age of 24 years having suffered a UTI requiring treatment and around 50 % of women having had an episode of UTI in their lifetime. Overall, UTIs are around twice as common in women as in men.
Invasive infections of the urinary tract, such as pyelonephritis, are less common, with around 250,000 cases per annum in the USA leading to around 200,000 admissions (1997 National Inpatient Sample database).
How Are Urinary Tract Infections Defined?
The mainstay of diagnosis of UTIs remains microscopy and culture of urine samples. The words used to describe UTIs are therefore generally couched in those terms (Table 1.1).
Table 1.1
Common definitions
|
Bacteriuria |
Bacteria in urine, as demonstrated by microscopy or quantitative culture |
|
Pyuria |
≥104 white blood cells per milliliter of urine |
|
Hematuria |
Blood in the urine, either visible to the naked eye (macroscopic) or invisible to the naked eye (microscopic) |
|
Significant bacteriuria |
≥104 colony-forming units/ml of bacteria (usually of a single species) in a fresh urine specimen |
|
Symptomatic bacteriuria |
Bacteria in urine in the context of typical symptoms of UTI |
|
Asymptomatic bacteriuria |
Bacteria in urine in the absence of symptoms of UTI on at least two consecutive occasions |
|
Urosepsis |
UTI with accompanying sepsis syndrome |
How May Urinary Tract Infections Be Classified and How Do These Assist in Clinical Management?
UTIs are generally classified according to their anatomical location or in terms of their severity and/or complexity.
Lower UTI, a term which encompasses cystitis and urethritis, is generally a benign condition that causes the typical symptoms of dysuria, suprapubic pain, frequency of micturition, urgency, hesitancy, and incomplete voiding. Systemic manifestations, such as fever, are uncommon and long-term sequelae are rare. It is usually treated with oral antibiotics which are excreted by the kidneys, thus reaching high levels in the urine, but not necessarily achieving high systemic or tissue levels.
Upper UTI or pyelonephritis is an invasive infection of the renal parenchyma, classically presenting with the triad of fever, renal angle tenderness, and nausea and vomiting. Lower urinary tract symptoms may or may not be present. Upper tract infections frequently cause urosepsis, and complications including kidney damage, abscess formation, and renal failure are common. Most cases will require admission and treatment with intravenous antibiotics that treat both the urinary and systemic components of the infection.
Uncomplicated UTIs are generally defined as lower tract infections affecting women with no structural, metabolic, or immunological predispositions. Some authorities also group cases of pyelonephritis with no complications in this category. Uncomplicated UTIs can be treated with narrower spectrum, oral antibiotics for short courses.
Complicated UTIs are those that involve the upper urinary tract and/or occur in individuals with predisposing factors such as structural and functional abnormalities, metabolic disorders, or impaired immunity. UTIs in children and men are often considered within this group, as UTI in these individuals is more frequently associated with predisposing factors, including congenital abnormalities in children and prostatitis in men. Many cases will require more protracted courses of broader spectrum antibiotics as multiresistant organisms are more common causes of these infections.
Recurrent UTIs: many women suffer recurrent infections. Recurrences may be divided into “relapses” where symptoms recur on cessation of treatment and the same organism is isolated or “reinfection” where a new causative organism is isolated. These patients are often exposed to multiple course of antibiotics or long-term antibiotic prophylaxis and may therefore rapidly develop infections with multiresistant organisms that render antibiotic choice problematic. In these cases, it may be important to explore non-pharmacological methods to reduce recurrences, such as improved hygiene and cranberry juice.
Why Do Urinary Tract Infections Occur?
There are two major routes by which microbial pathogens can infect the urinary tract: ascending spread of fecal flora and hematogenous spread. In addition to this, a variety of host factors affecting urine flow and local immunity predispose to colonization and infection by bacteria.
By far the most common route of infection is migration of organisms from the perineum via the urethra to the bladder and then to the kidney. Around 95 % of UTIs are thought to arise in this way. This explains the much greater incidence in young sexually active women in whom uropathogenic bacteria from the fecal flora are physically translocated via the short female urethra to infect the normally sterile urinary tract.
Only around 5 % of cases are due to infection following bacteremia. A number of pathogens, such as Mycobacterium tuberculosis, can spread to the renal tract in this way, although these are uncommon in the developed world.
Which Organisms Cause Urinary Tract Infections?
The majority of bacteria causing UTIs originate from the bowel, with a small percentage arising from skin flora (Table 1.2). Most data regarding mechanisms of pathogenicity have been obtained by study of E. coli which is the most common cause of both uncomplicated and complicated UTI. Bacteria express a variety of surface proteins, known as adhesins, which allow them to cling to epithelial cells. Uropathogenic E. coli may, for example, express P fimbriae which attach to globoseries-type glycolipids on urinary epithelium. These are found more commonly in strains that cause urosepsis. Other virulence factors, such as capsular polysaccharides, may protect against host defenses such as opsonization and phagocytosis, while a number of toxins, including alpha hemolysin and cytotoxic necrotizing factor 1, may be involved in local cellular damage.
Table 1.2
Types of bacteria causing urinary tract infection
|
% Uncomplicated |
% Complicated |
|
|
Gram negative |
||
|
Escherichia coli |
70–95 |
21–54 |
|
Proteus mirabilis |
1–2 |
1–10 |
|
Klebsiella spp. |
1–2 |
2–17 |
|
Citrobacter spp. |
<1 |
5 |
|
Enterobacter spp. |
<1 |
2–10 |
|
Pseudomonas aeruginosa |
<1 |
2–19 |
|
Others |
<1 |
6–20 |
|
Gram positive |
||
|
Staphylococcus saprophyticus |
5–10 |
1–4 |
|
Enterococcus spp. |
1–2 |
1–23 |
|
Group B streptococcus |
<1 |
1–4 |
|
Staphylococcus aureus |
<1 |
1–23 |
|
Others |
<1 |
2 |
Adapted from. [9]
Why Are Some Individuals More at Risk of Urinary Tract Infections?
UTIs occur when bacteria enter the urinary tract. If this happens more frequently or a greater bacterial load is introduced, for example, in sexually active women, poor hygiene, or instrumentation, the incidence of UTI increases. Furthermore, while host defenses (both physical and immunological) often destroy these pathogens before they establish an infection, impairment of these mechanisms will also predispose to infection. Predisposing factors include:
1.
2.
3.
4.
Which Antibiotics Are Used for Empirical Treatment of Urinary Tract Infections?
Empirical antibiotics are those chosen when the exact causative organism and resistance pattern is unknown. In the case of UTI, the choice of antibiotics depends on a number of factors, including the relative prevalence of uropathogenic organisms, the local resistance patterns and levels of resistance previously observed, the clinical syndrome with which the patient presents and the origin of the infection, whether community-acquired or nosocomial. An empirical antibiotic for the treatment of UTIs should therefore have activity against the Gram-negative Enterobacteriaceae (such as E. coli and Klebsiella spp.) and Gram-positive organisms including Staphylococcus saprophyticus and ideally Enterococcus spp.
Uncomplicated, lower UTIs can be treated with oral antibiotics and should be restricted to short courses of 3–5 days if possible. Antibiotics such as nitrofurantoin, trimethoprim, and first-generation cephalosporins such as cephalexin are concentrated in the urine and therefore reach high levels above the minimum inhibitory concentrations (MIC) of most community-acquired organisms. The proportion of organisms found to be resistant to amoxicillin in most areas is now too high for this to be used as empirical therapy, although it is still the drug of choice for the treatment of most infections with Enterococcus faecalis. In some areas, resistance to trimethoprim, nitrofurantoin, and cephalexin is approaching levels where their use as empirical antibiotics may no longer be desirable, and alternative choices, such as quinolones, may be required.
Complicated UTIs require therapy with antibiotics that reach high systemic levels in order to treat bacteremia and invasive tissue infections such as pyelonephritis. Commonly used antibiotics include second-generation cephalosporins such as cefuroxime, co-amoxiclav, or ciprofloxacin. These may be supplemented with an aminoglycoside, such as gentamicin, which confers the benefit of rapid bactericidal activity as well as the addition of a second antibiotic class, thus increasing the likelihood of having treated early with an effective empirical antibiotic.
The exact choice of empirical antibiotics is highly dependent on the likelihood of resistant mutants within both the community and the individual patient. It is therefore important to take a full clinical history, as certain patient groups may require early treatment with broad-spectrum antibiotics. In particular, patients who have had recent inpatient admissions, recurrent courses of antibiotics, or reside in nursing homes are all at greater risk of infection with multiresistant organisms, including extended-spectrum beta-lactamase (ESBL) and AmpC producers (see below).
Why Is Bacterial Culture and Sensitivity Testing Important?
Empirical antibiotics are chosen on the basis of being sufficiently broad spectrum to treat the majority of UTIs in a patient group but sufficiently narrow spectrum to minimize attendant adverse effects, such as Clostridium difficile-associated diarrhea. However, for a proportion of cases, the first-line antibiotic choice will either be excessively broad (in the case of infection with very sensitive organisms) or have insufficient activity (where infecting organisms have intrinsic or acquired resistance). In both situations, it is desirable to have identified the causative organism and its sensitivity pattern so that antibiotic therapy can be rationalized appropriately.
How Has Antibiotic Resistance Arisen in Bacteria?
Many bacteria are intrinsically resistant to certain classes of antibiotics. These are due to characteristics encoded on the bacterial chromosome and include structural features, such as the outer membrane of most Gram-negative organisms which prevents penetration of vancomycin; the absence of antibiotic targets, such as the absence of cell wall in Chlamydia spp.; and membrane proteins such as efflux pumps that actively exclude antibiotics from the bacterial cell. Intrinsic resistance mechanisms are common to all members of a bacterial species and are not easily transferred to other species. They are therefore perceived as a lesser infection control risk.
The widespread use of antibiotics in medicine and agriculture has led to massive selection pressure on bacteria in our environment. Many organisms have acquired resistance mechanisms by either mutation or transfer of resistance genes via transposable genetic elements, including transposons and plasmids, which can spread rapidly within bacterial cells and between bacterial species. Many resistance genes are transferred together on the same plasmid and can therefore lead to the acquisition of multiple resistance phenotypes in a single step.
The most prevalent acquired resistance mechanisms are:
1.
2.
3.
What Are Extended-Spectrum Beta-Lactamases (ESBLs)?
A number of Gram-negative bacteria possess intrinsic beta-lactam resistance mediated by chromosomal beta-lactamase genes which probably evolved in response to organisms such as beta-lactam-producing fungi [3]. However, the rapid spread of beta-lactamases is primarily due to the appearance of plasmid-mediated beta-lactamase genes, the first of which was discovered in the 1960s in E. coli and named TEM-1 [4]. Other beta-lactamases such as SHV-1, which is chromosomal in Klebsiella pneumoniae but generally plasmid-encoded in E. coli, have also become increasingly common.
As these resistant organisms became a clinical problem, newer classes of antibiotics were developed with the specific intention of overcoming their resistance mechanisms. However, the pressure that these novel antibiotics exerted quickly led to the selection of mutants with beta-lactamase variants which were now able to hydrolyze them. In the mid-1980s, the first ESBL (SHV-2) was identified in a strain of Klebsiella ozaenae [5]. Functionally, organisms possessing these enzymes are resistant to third-generation cephalosporins but are inhibited by clavulanate which allows them to be identified on phenotypic testing.
The presence of ESBL genes on mobile genetic elements has allowed their rapid spread and also led to wide geographical variability in their incidence. While up to 40 % of K. pneumoniae isolates in France are resistant to ceftazidime [6], less than 1 % of E. coli and K. pneumoniae in the Netherlands are ESBL-producers [7]. In the United Kingdom during the 1990s, reports of resistant Gram-negative organisms with the ESBL phenotype were mainly derived from cases of nosocomial infection, primarily from intensive care units. These were caused by organisms carrying TEM or SHV genes and although intermittent outbreaks did occur these were not considered a widespread clinical problem [8].
In 2000, the first CTX-M gene was identified in the UK from an isolate of K. oxytoca and was rapidly followed by the emergence of ESBLs as a significant public health issue. By 2003, many laboratories in the UK were reporting organisms possessing CTX-M genes isolated from community patients, which differed markedly from the preceding trend in ESBLs. These organisms frequently also possessed other resistance mechanisms protecting them from the effects of quinolones and aminoglycosides.
What Are AmpC Beta-Lactamases and Which Organisms Produce Them?
ESBLs of the CTX-M group show significant structural similarity to AmpC beta-lactamases which are encoded on the chromosomes of several species of Enterobacteriaceae (Table 1.3).
Table 1.3
Bacteria with chromosomally encoded, inducible AmpC beta-lactamase
|
Enterobacter spp. |
|
Serratia spp. |
|
Citrobacter spp. |
|
Acinetobacter spp. |
|
Providencia spp. |
|
Pseudomonas spp. |
|
Morganella spp. |
In the majority of these, the AmpC gene is under the control of an inducible promoter and is therefore only produced at high levels when stimulated by the presence of antibiotics locally. More recently, mutations in the promoter have led to strains producing constitutively high levels of AmpC beta-lactamase. These genes have also increasingly transferred to plasmids which have spread to E. coli and Klebsiella spp., where again the protein is expressed at high levels, conferring resistance to all penicillins and first-, second-, and third-generation cephalosporins.
Which Antibiotics May Be Effective Against ESBL and AmpC Producers?
Carbapenems, including meropenem, imipenem, and ertapenem, are generally considered the treatment of choice for multiresistant Enterobacteriaceae. Although ESBLs are blocked by beta-lactamase inhibitors such as clavulanic acid and tazobactam, antibiotic combinations containing these are unreliable in vivo. These organisms are sometimes sensitive to quinolones and aminoglycosides, in which case they may be used to spare carbapenem use, but often there are few choices of antibiotics available against very resistant isolates.
The increasing use of carbapenems has inevitably encouraged the appearance of carbapenemase-producing organisms. In order to reduce the reliance on this drug class and the resulting selection pressure, newer antibiotics have been developed such as tigecycline, and older drugs have been resurrected (e.g., temocillin) which are resistant to hydrolysis by ESBLs and AmpCs, although resistance against these antibiotics also exists. In the case of multiresistant Pseudomonas spp. or Acinetobacter baumannii, which can carry multiple resistance mechanisms and has caused severe nosocomial outbreaks, it may be necessary to treat with more toxic drugs such as colistin.
What Are Vancomycin-Resistant Enterococci (VRE)?
Use of cephalosporins selects for enterococci which are part of the normal bowel flora and are intrinsically resistant to cephalosporins. They have therefore become more common as causes of UTI. Furthermore, increased nosocomial use of vancomycin for the treatment of MRSA and C. difficile-associated diarrhea has encouraged the spread of VREs which are commonly resistant to all glycopeptides with variable sensitivity to aminopenicillins, depending on the species. Although often found colonizing non-sterile sites rather than truly causing infections, antibiotic choice is limited when treating VREs.
What Antibiotics May Be Effective Against VRE?
If the isolate is sensitive, amoxicillin is the treatment of choice for VRE. However, although the most commonly isolated species, Enterococcus faecalis, is usually sensitive to amoxicillin, most others are not. Conversely, E. faecalisis intrinsically resistant to quinupristin/dalfopristin (Synercid) while other species are sensitive.
Linezolid is now widely used for infections with amoxicillin-resistant VRE. Other newer antibiotics including tigecycline and daptomycin also have activity against most isolates.
Key Points
· Urinary tract infections are very common.
· They are most common in sexually active women, young children, and the elderly.
· UTIs are usually due to translocation of bacteria originating from the bowel ascending into the urinary tract.
· Lower, uncomplicated UTIs have no long-term sequelae and are generally treated with short courses of oral antibiotics.
· Pyelonephritis, urosepsis, and other complicated UTIs usually require hospital admission and intravenous antibiotics.
· Urine and blood culture with sensitivity testing is essential in order to rationalize the antibiotic choice.
· Widespread antibiotic use has promoted the spread of resistance.
· Among the Gram-negative Enterobacteriaceae, the prevalence of ESBL and AmpC-producing organisms is increasing in both hospital and community settings.
· Multiresistant organisms may require treatment with very broad-spectrum antibiotics and newer antibiotic classes.
References
1.
Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Dis Mon. 2003;49:53–70.PubMedCrossRef
2.
Office of Population Censuses and Statistics. Morbidity statistics from general practice.Fourth national study 1991-92. London: OPCS, 1996.
3.
Ghuysen JM. Serine beta-lactamases and penicillin-binding proteins. Annu Rev Microbiol. 1991;45:37–67.PubMedCrossRef
4.
Marchandin H, Carriere C, Sirot D, Pierre HJ, Darbas H. TEM-24 produced by four different species of Enterobacteriaceae, including Providencia rettgeri, in a single patient. Antimicrob Agents Chemother. 1999;43:2069–73.PubMed
5.
Kliebe C, Nies BA, Meyer JF, Tolxdorff-Neutzling RM, Wiedemann B. Evolution of plasmid-coded resistance to broad-spectrum cephalosporins. Antimicrob Agents Chemother. 1985;28:302–7.PubMedCrossRef
6.
Branger C, Lesimple AL, Bruneau B, Berry P, Lambert-Zechovsky N. Long-term investigation of the clonal dissemination of Klebsiella pneumoniae isolates producing extended-spectrum beta-lactamases in a university hospital. J Med Microbiol. 1998;47:201–9.PubMedCrossRef
7.
Stobberingh EE, et al. Occurrence of extended-spectrum betalactamases (ESBL) in Dutch hospitals. Infection. 1999;27:348–54.PubMedCrossRef
8.
Livermore DM, Hawkey PM. CTX-M: changing the face of ESBLs in the UK. J Antimicrob Chemother. 2005;56:451–4.PubMedCrossRef
9.
Hooton TM. The current management strategies for community-acquired urinary tract infection. Infect Dis Clin North Am. 2003 Jun;17(2):303–32. Review.PubMedCrossRef