Forum
Clinical Review
Current concepts in the
treatment of UTIs
Local resistance patterns to E. coli are
important in selecting the appropriate
antibiotic, write Tadhg-Iarla Curran,
Fardod O’Kelly and Ciaran Brady
Urinary tract infections (UTIs) are the second most
common infection encountered by GPs. It has been shown
that the suitability of UTI treatment by GPs in Ireland may
be as low as 55%, where an appropriate treatment was
subsequently verified by a sensitive culture result. 1 The
importance of recognising the appropriate patient to treat
and the application of antimicrobial stewardship has farreaching implications for microbial resistance in Ireland.
UTI symptoms can be classified into:
• C ystitis – dysuria, frequency, haematuria, urgency,
suprapubic pain
• Pyelonephritis – flank pain, fevers, rigors, nausea, vomiting and costovertebral angle tenderness.
For women with a structurally and functionally normal urinary tract, cystitis and mild pyelonephritis are considered
uncomplicated UTIs. UTIs in men, older people, pregnant
women, children or patients who have an indwelling catheter or an anatomic or functional abnormality, are considered
complicated UTIs.2
The gold standard for the diagnosis of a UTI is the detection of the causal pathogen in the presence of clinical
symptoms. This is most reliably done using a clean catch
(mid-stream) urine specimen. Based on symptoms alone
the probability of cystitis is greater than 50% in women
with any lower urinary tract symptom and greater than 90%
in women who complain of both frequency and dysuria.3
The use of urinalysis to diagnose a UTI is unreliable and
should only be used in the presence of symptoms. Urine
dipstick is most sensitive when positive for both leukocyte
esterase and nitrite (sensitivity 75%, specificity 82%).3
Urinalysis should be avoided in asymptomatic patients
and in those with catheters as this will lead to a high false
positive rate. A urine culture should be sent in all symptomatic patients with a positive dipstick result. A positive
urine culture is typically defined as >105 cfu/mL of a single
organism with >105 organisms per high power field on uri40 FORUM November 2013
nalysis. A positive culture in the absence of symptoms is
defined as bacteriuria. Bacteriuria should not be treated
except in the case of pregnancy. Red cells may be present
in infection but persistent red cells should be referred for
investigation to outrule other causes, including neoplasia.
Recent culture and sensitivity results may help guide
treatment in recurrent infection. In patients re-presenting within three months with a previous sample showing
an Escherichia coli (E. coli) resistant to ampicillin, trimethoprim or ciprofloxacin, their recurrent UTI is likely
to be associated with an organism that is still resistant. If
a patient with a recurrent UTI was diagnosed in the previous year with an E. coli isolate that was susceptible to
nitrofurantoin, ciprofloxacin or trimethoprim, the organism
associated with this recurrent episode is likely to be still
susceptible.4
Special cases
There are a number of scenarios where the principles of
treatment are different from uncomplicated UTIs. Bacteriuria is seen in 2-7% of pregnancies and has a similar
aetiology to non-pregnant women. It is associated with an
increased risk of preterm birth, low birth weight and perinatal mortality. Screening with urine dipsticks does not come
close to the accuracy and reliability of a carefully handled
clean-catch culture specimen.5 Penicillin, cephalosporins
and fosfomycin are generally accepted to be safe in pregnancy. Trimethoprim is a folic acid antagonist and should
be avoided in the first trimester. Treatment should be prescribed for a seven day course and pathogen eradication
should be confirmed on repeat culture.
UTIs present commonly in children and are a challenging clinic scenario. Children present most commonly with
fever, which makes cystitis and pyelonephritis difficult to
distinguish.6 Pyelonephritis may lead to serious sequelae,
including renal scarring, hypertension and chronic kidney
disease. UTIs in children have been shown in all stud-
Forum
Clinical Review
ies to necessitate early (within 72 hours) and aggressive
antibiotic treatment to avoid long term complications. The
choice of antibiotic therapy should be administered on
a case by case basis in the context of local resistance
patterns. Third generation cephalosporins are appropriate first-line empiric therapy in children but do not cover
enterococcus infection most often seen in instrumentation
or anatomical abnormality, and in these cases amoxicillin
should be added. The mean time to response is 24-48
hours after initiation of antibiotics. All children under
three months of age, with upper UTI or at risk of serious
illness as per the NICE guidelines, should be referred to
specialist care.7
Common pathogens and pitfalls with resistance
E. coli is the most common pathogen causing a UTI and is
responsible for approximately 80% of community and 40%
of nosocomial infections. Klebsiella, Proteus and Enterobacter are less prevalent.8 Knowledge of local resistance
patterns to E. coli is important in selecting the appropriate
antibiotic, as large inter-regional variability exists.
Similar E. coli resistance patterns have been demonstrated in both the West of Ireland and Dublin regions in
the past decade. Both ampicillin and trimethoprim are the
least active agents against E. coli and have demonstrated
more than 50% and 30% resistance respectively, making
them unsuitable agents for empiric treatment of UTIs.9
Some 40% were resistant to sulphonamides. In addition,
7.9% of community isolates and 12.5% of nosocomial isolates were resistant to co-amoxiclav. Trends of resistance
have been increasing over an 11-year period for ampicillin, trimethoprim, gentamicin and ciprofloxacin. Significant
differences in co-amoxiclav, gentamicin, nitrofurantoin and
ciprofloxacin resistance rates were also noted depending on
the sample origin in the Dublin region.8 In the study in the
West of Ireland, E. coli remained susceptible to nitrofurantoin (96%), nalidixic acid (94%) and ciprofloxacin (94%).
The rates of resistance were higher in the Dublin area where
ciprofloxacin resistance rates reach 10%.
Empiric treatment should be based on local resistance
rates where available. Generally speaking, nitrofurantoin
remains a reliable empiric treatment and should be considered as a firstline agent for initial and repeat treatment.
Resistance to nitrofurantoin is low and, once detected,
decays relatively quickly. Sensitivity to nitrofurantoin has
remained greater than 95% with little change over the past
decade. It has been shown to be as effective as any other
initial treatment choice, including ciprofloxacin for UTIs.4
With the results of culture and sensitivity and depending on
the patient’s response, treatment can be altered if empiric
treatment does not improve symptoms.
Common urinary antibiotics
Nitrofurantoin (monohydrate/macrocrystals 100mg BD for
five days) is a urinary-specific antibiotic with a broad antibacterial ribosomal mechanism of action. The nature of this
mode of action may explain the lack of acquired bacterial
resistance to nitrofurantoin. Nausea can be a problem but
may be overcome by taking with milk at bedtime or using
the macrocrystalline form. It should be avoided if there is
suspicion of early pyelonephritis. It is contraindicated if
creatinine clearance is <60ml/min. Prolonged use may be
complicated by rare pulmonary reactions and hepatitis.
42 FORUM November 2013
Table 1: Practice points
• Diagnosis of a UTI requires the growth of bacteria in the
presence of symptoms
• Asymptomatic bacteriuria should not be treated, except
in the case of pregnancy
• All children under three months and those at risk of
serious illness should be referred to a specialist
• Nitrofurantoin remains a viable firstline empiric
treatment
• Fosfomycin is a valid second line empiric treatment for
cystitis
• Antimicrobial prophylaxis does not alter baseline
susceptibility but may give a symptom-free period at the
risk of exposing the patient to antimicrobial side effects
• Referral should be considered in cases of complicated,
resistant or recurrent uncomplicated UTIs
Fluoroquinolones, including ciprofloxacin 500mg BD or
1,000mg extended release OD for five to 15 days, have
broad spectrum activity against most organisms with a
predominantly gram negative effect. These drugs cause an
increased risk of tendon rupture and tendonitis, particularly
in the elderly and in those on steroids. They should also be
avoided in those with myasthenia gravis as they exacerbate
muscle weakness.
Trimethoprim (200mg BD for three days) inactivates
folic acid. It has inhibitory activity for most gram-positive
aerobic cocci and some gram-negative aerobic bacilli. Skin
eruptions and gastrointestinal disturbance are the most
common adverse effects associated with its use.
Penicillin, including co-amoxiclav (625mg TDS for three
days), should be considered second-line agents in the
treatment of UTIs, given problems with resistance. Diarrhoea, skin reactions, genital itching and vaginal problems
are some of the adverse effects. Co-amoxiclav is also more
expensive than some of the other drugs listed.
Fosfomycin trometamol
Fosfomycin trometamol is a cost-effective, well-tolerated
and effective chemical compound which should be considered second choice in empiric treatment of uncomplicated
cystitis after nitrofurantoin. It is typically taken as a single
dose at bedtime. The drug is excreted unaltered in the urine
and achieves therapeutic urinary concentrations from two
to at least 48 hours, which is sufficient to inhibit most
pathogens.10
Many factors may have contributed to preserve the antibacterial activity of fosfomycin trometamol, including single
dose usage limited to urinary infections and very high and
sustained urinary concentrations that rapidly kill bacteria,
reducing the opportunity for mutant selection. In addition,
there is no animal feed that contains the drug, resistance
is most commonly acquired by chromosomal mutations
that do not spread easily, and the biological cost of these
genetic modifications is high. 11 It is suitable for use in
pregnancy and only minor adverse effects have been noted
(rash, nausea, rhinitis and vaginitis) in 1-10%. Worldwide,
E. coli resistance to fosfomycin is approximately 1%. It is
likely this often-overlooked antimicrobial will come to the
forefront of treatment in time, given the spiralling trends of
resistance seen in recent years.
Prevention
Recurrent UTIs (rUTIs) are traditionally defined as
more than three per year or more than two in a six-month
period. As many as 30-44% of women who have a UTI
will have a recurrence often within six months. Conservative preventative measures such as adequate hydration,
regularly voiding, the avoidance of feminine hygiene
products such as douches, postcoital voiding and use of
non-perfumed soaps may be advisable. There is little evidence to suggest cranberry juice is effective in reducing
UTI recurrence.12
Long-term antimicrobial prophylaxis does not reduce the
patient’s baseline level of susceptibility, as rates of infection
return to pre-treatment levels once stopped. Prophylaxis is
associated with exposure to adverse drug reactions, such
as pulmonary fibrosis and hepatitis in the case of nitrofurantoin. One modern strategy is to promote self diagnosis
and treatment initiation in patients with known high rates
of rUTIs, which has been shown to be effective, although
further evidence is required before this becomes a more
widespread approach.13
Reasons for referral
Referral to tertiary care should be considered in the case
of all complicated UTIs, recurrent UTIs, severe resistance
lower UTIs, all cases of pyelonephritis except in the case
of mild infection in a structurally normal kidney which
responds to appropriate antibiotic therapy, persistent
haematuria, and all children under three months or with
markers of a serious illness
Tadhg-Iarla Curran is a GP trainee, Fardod O’Kelly is a urology
specialist registrar and Ciaran Brady is a reconstructive and
paediatric urological consultant surgeon at Mercy University
Hospital, Cork
References
1. Vellinga A, Cormican M, Hanahoe B, Bennett K, Murphy AW. Antimicrobial management and appropriateness of treatment of urinary tract infection
in general practice in Ireland. BMC Fam Pract 2011; 12(1):108
2. Gupta K, Hooton TM, Naber KG, et al. International clinical practice
guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of
America and the European Society for Microbiology and Infectious Diseases.
Clin Infect Dis 2011; 52:e103
3. Scholes D, Hooton TM, Roberts PL, et al. Risk factors associated with
acute pyelonephritis in healthy women. Ann Intern Med 2005; 142:20
4. Vellinga A, Cormican M, Hanahoe B, Murphy AW. Predictive value of antimicrobial susceptibility from previous urinary tract infection in the treatment
of re-infection. Br J Gen Pract 2010; 60(576):511-3
5. McNair RD, MacDonald SR, Dooley SL, Peterson LR. Evaluation of the
centrifuged and Gram-stained smear, urinalysis, and reagent strip testing to
detect asymptomatic bacteriuria in obstetric patients. Am J Obstet Gynecol
2000; 182:1076
6. Hoberman A, Charron M, Hickey RW, et al. Imaging studies after a
first febrile urinary tract infection in young children. N Engl J Med 2003;
348:195
7. NICE Guidelines: Urinary Tract Infection in Children. Issue date:
August 2007. Accessed online at http://www.nice.org.uk/nicemedia/
live/11819/36032/36032.pdf
8. Cullen IM, Manecksha RP, McCullagh E, Ahmad S, O’Kelly F, Flynn RJ et
al. The changing pattern of antimicrobial resistance within 42,033 Escherichia coli isolates from nosocomial, community and urology patient-specific
urinary tract infections, Dublin, 1999-2009. BJU International 2012;
109(8):1198-206
9. Curran T. Antimicrobial resistance…ct-Dec] - PubMed - NCBI
10. Raz R. Fosfomycin: an old-new antibiotic. Clinical Microbiology and
Infection 2012; 18(1):4-7
11. SCHITO G. Why fosfomycin trometamol as first line therapy for uncomplicated UTI? Int J Antimicrobial Agents 2003; 22:79-83
12. Gupta K, Trautner BW. Diagnosis and management of recurrent urinary
tract infections in non-pregnant women. BMJ 2013; 346(May 29 4):f3140
13. Nickel JC. Practical Management of Recurrent Urinary Tract Infections
in Premenopausal Women. Rev Urol 2005; 7:11-17