Coralie Therese D.
Dimacali, MD, FPCP, FPSN
A 28 year old non-pregnant female
consults at your OPD clinic for pain
on urination on waking up. She
also complains of frequency and
blood-tinged urine. (-) vaginal
discharge, (-) fever. Past history
and PE are unremarkable.
How would you manage her?
Present the Philippine Clinical
Practice Guidelines on the Diagnosis
and Management of Acute
uncomplicated cystitis (AUC)
Discuss Nitrofurantoin as first line
therapy for the management of AUC
PSMID, POGS, PSN, PUA, PAFP
Chair: Dr. Mediadora C. Saniel
Co-chair: Dr. Marissa M. Alejandria
Strength of recommendations
STRONG : desirable effects (benefits) outweigh
undesirable effects (risk)
CONDITIONAL: desirable effects probably outweigh
undesirable effects, but the
recommendation is applicable only to a
specific group or setting OR the benefits
may not warrant the cost in all settings
WEAK : desirable and undesirable effects closely
balanced OR uncertain, new evidence may
change the balance of risk to benefit
NO RECOMMENDATION: Further research required
Quality of evidence
HIGH: Further research is very unlikely to change
confidence in estimate of effect
MODERATE: Further research is likely to have an
important impact on confidence in the
estimate of the effect
LOW: Further research is very likely to have an
important impact in the estimate of effect
and is likely to change the estimate
VERY LOW: Any estimate of effect is very uncertain
(case series; expert opinion)
Woman with ≥1
symptoms of UTI*
Pregnant? See Section on UTI in pregnancy
Recurrent
See Section on Recurrent UTI
≥2x/year?
Do urinalysis, urine culture to establish diagnosis
With risk factors for
Consider initiating empirical treatment
complicated UTI?
See Section on Complicated UTI
Urinary catheterization
Incomplete bladder emptying >100 ml post-void
residual urine
Impaired voiding due to neurogenic bladder,
cystocoele
Obstructive uropathy
Vesicoureteral reflux & other urologic
abnormalities
Chemical or radiation injuries of the
uroepithelium
Peri- or post-operative UTI
Azotemia due to intrinsic renal disease
Renal transplantation
Diabetes mellitus
Immunosuppressive conditions – e.g. febrile
neutropenia, HIV-AIDS
UTI caused by unusual pathogens (M.
tuberculosis, Candida spp.)
UTI caused by antibiotic-resistant or multi-drug
resistant organisms (MDROs)
UTI in males except in young males presenting
exclusively with lower UTI symptoms
Urosepsis
Woman with ≥1
symptoms of UTI*
Pregnant? See Section on UTI in pregnancy
Recurrent
See Section on Recurrent UTI
≥2x/year?
Do urinalysis, urine culture to establish diagnosis
With risk factors for
Consider initiating empirical treatment
complicated UTI?
See Section on Complicated UTI
Consider Acute Uncomplicated Pyelonephritis
With flank pain or Do urinalysis, urine culture to establish diagnosis
fever? Consider empiric treatment
See Section on Acute Uncomplicated Pyelonephritis
Low to intermediate probability of UTI (~20%)
Consider Sexually Transmitted Infections
With vaginal Do pelvic examination (including cervical culture
discharge? when appropriate), urinalysis, urine culture, urine
Chlamydia to establish diagnosis
See Section on Acute Uncomplicated Cystitis
Woman with ≥1
symptoms of UTI*
Low to intermediate probability of UTI (~20%)
Consider Sexually Transmitted Infections
With vaginal Do pelvic examination (including cervical culture when
appropriate), urinalysis, urine culture, urine Chlamydia to
discharge?
establish diagnosis
See Section on Acute Uncomplicated Cystitis
With clear history of
≥ 1 symptoms of UTI – High probability of AUC (~90%)
acute onset of dysuria, Start empiric treatment without urinalysis, urine culture
frequency, urgency, See Section on Acute Uncomplicated Cystitis
hematuria?
Perform dipstick urinalysis
High probability of AUC (~80%)
Dipstick result
Start empiric treatment without urine culture
positive?
See Section on Acute Uncomplicated Cystitis
Low to intermediate probability of UTI (~20%)
Consider urine culture or close clinical follow-up and pelvic examination including
cervical cultures and radiologic imaging when appropriate
See Section on Uncomplicated Urinary Tract Infection
1. When is AUC suspected in women?
2. What is the best approach in the management of a
patient suspected to have AUC?
3. Which antibiotics are effective for AUC?
4. What is the effective duration of treatment for
AUC?
5. In elderly women (>65 years) with AUC what is
the effective duration of treatment?
6. What should be done for women whose symptoms
worsen, do not completely resolve or do not
improve after completion of treatment?
7. What is the clinical utility of a post-treatment
urine culture?
When is AUC suspected in women?
◦ Clinically, AUC is suspected in premenopausal non-
pregnant women presenting with acute onset of
dysuria, frequency, urgency, and gross hematuria; and
without vaginal discharge.
◦ Urinalysis is not necessary to confirm the diagnosis of
AUC
◦ Women presenting with urinary symptoms plus
vaginal discharge should undergo further evaluation.
◦ Risk factors for complicated UTI must be absent
Strong recommendation
High quality of evidence
Blover et al Urological Science 2014); 25:1-8
What is the best approach in the management
of a patient suspected to have AUC?
◦ Empiric antibiotic treatment is the most cost-
effective approach in the management of AUC.
◦ Pre-treatment urine culture and sensitivity is NOT
recommended.
◦ Standard urine microscopy and dipstick leukocyte
esterase (LE) and nitrite tests are not
prerequisites for treatment.
Strong recommendation
High quality of evidence
1. empirical immediate antibiotic
2. empirical antibiotic if patient still
symptomatic after 48 hours (empirical
delayed)
3. empirical immediate if with symptom score ≥
2 (cloudy urine, smelly urine, nocturia,
dysuria)
4. empirical antibiotic if dipstick positive (nitrite
or leucocytes and blood)
5. culture guided antibiotic treatment
Little P, et al. Effectiveness of five different approaches in management of
urinary tract infection: randomised controlled trial. BMJ. 2010.
Results:
There was no significant difference in the severity of
symptoms
Patients who waited 48 hours to start taking
antibiotics had moderately bad symptoms 37% longer
than those taking immediate antibiotics; culture-
guided group , 73% longer
No major adverse events for any group
Conclusion:
All management strategies achieved similar symptom
control
Found no advantage in routinely sending midstream
urine sample for laboratory testing
Little P, et al. Effectiveness of five different approaches in management of
urinary tract infection: randomised controlled trial. BMJ. 2010.
Conclusion:
All management strategies for urinary tract
infection have similar resource
implications.
Turner D. Cost effectiveness of management strategies for urinary
tract infections: results from randomised controlled trial. BMJ. 2010
Which antibiotics are effective for acute
uncomplicated cystitis?
o Efficacy in terms of clinical cure, cost effectiveness,
safety and tolerability were considered in the choice of
antibiotics . In addition, the propensity to cause
collateral damage and local susceptibility rates were
given greater weights in the choice of antibiotic
recommendations.
Strong recommendation
High quality of evidence
Collateral damage is the “ecological adverse effect” of antibiotic
therapy. Such adverse effects include selection of drug-resistant
organisms and colonization or infection with multi-drug
resistant organisms.
Which antibiotics are effective for acute
uncomplicated cystitis?
o Ampicillin or amoxicillin should NOT be used for
empirical treatment given the relatively poor
efficacy and very high prevalence of antimicrobial
resistance to these agents worldwide.
Strong recommendation
High quality of evidence
Which antibiotics are effective for acute
uncomplicated cystitis?
o Trimethoprim-sulfamethoxazole 160/800 mg
BID for three days should be used ONLY for
culture-proven susceptible uropathogens due to
high prevalence of local resistance and high
failure rates.
Strong recommendation
High quality of evidence
90
81.5
80
74.3
70 65.8
64.1
60
53.4
49
50
41.4
38.9
40
29.2 28
30 27
25.4 25.3 25.4
20.9
20 17
11.6 11.6 11.8
10 6.6 6.6 8.1
5.1 5.6 5.1
1.7
0
UUTI Study, 2010-2011, N=181 TMC, 2010-2011, N=700 ARSP, 2011, N=775
Figure 2. Clinical outcomes in women with aTMP-SMX–susceptible vs
TMP-SMX–nonsusceptible isolate
Gupta K et al. Short-Course Nitrofurantoin for the Treatment
of Acute Uncomplicated Cystitis in Women. Arch Intern Med.2007.
Trimethoprim-sulfamethoxazole (TMP-
SMX) is an appropriate choice for acute
uncomplicated cystitis if TMP-SMX
resistance rate does not exceed 20% in
the locality
Gupta K. Emerging antibiotic resistance in urinary tract pathogens.
Infect Dis Clin North Am.2003.
Raz R et al. Empiric use of TMP-SMX in the
treatment of women with UTI. Clin Infect Dis 2002.
Which antibiotics are effective for acute uncomplicated
cystitis?
o Nitrofurantoin monohydrate/macrocrystals (100 mg
BID for five days) is recommended as the first line
treatment for AUC due to its high efficacy, minimal
resistance, minimal adverse effects, low propensity
for collateral damage and reasonable cost. However,
the nitrofurantoin monohydrate/macrocrystal
formulation is not locally available. Thus
nitrofurantoin macrocrystal formulation 100 mg is
recommended, but it should be given four times a
day for five days.
Strong recommendation
High quality of evidence
A synthetic
.
H2O nitrofurane
derivative
Specific for UTI
Bacteriostatic at low
concentrations
Bactericidal at high
concentrations
Chemical structure
Readily absorbed from the GI tract after oral
administration, improved (40%) when taken with
food
25-60% of the drug is protein bound
Plasma T/2 is about 20 minutes
75% metabolized in the liver; 25% rapidly
excreted in the urine
Antimicrobial concentrations are not reached in
the blood
Concentrated in the urine where bactericidal
concentration is achieved
its reduced form, nitrofuran, damages
bacterial DNA
bind to ribosomal proteins, and inhibit
bacterial respiration and pyruvate
metabolism and other
macromolecules within the cell
Known hypersensitivity to nitrofurans
Pre-existing pulmonary, hepatic, neurological
or allergic disorders
Elderly
Impaired renal function
Oplinger and Andrews, Ann Pharmacother 2013; 47:106-11
Known hypersensitivity to nitrofurans
Pre-existing pulmonary, hepatic, neurological
or allergic disorders
Elderly
Impaired renal function
Pregnancy at term – may cause hemolytic
anemia in the neonate
Nursing mothers of infants with G6PD
deficiency
Should not be given together with quinolones
Nausea, vomiting, anorexia, abdominal pain,
diarrhea
Headache, drowsiness, vertigo, dizziness,
nystagmus, intracranial hypertension
Skin rash, urticaria, pruritus, fever,
angioedema
Anaphylaxis, erythema multiforme, Steven
Johnson syndrome, exfoliative dermatitis,
pancreatitis, lupus-like syndrome, myalgia,
arthralgia, acute asthmatic attacks
Fever, chills, eosinophilia, cough, chest pain,
dyspnea, pulmonary infiltration or
consolidation, pleural effusion
Subacute or chronic pulmonary symptoms
including interstitial pneumonitits and
pulmonary fibrosis
Hepatotoxicity including cholestatic jaundice
and hepatitis
Megaloblastic anemia, leukopenia,
granulocytopenia, agranulocytosis,
thrombocytopenia, aplastic anemia and
hemolytic anemia in patients with a genetic
deficiency of G-6-phosphate
dehydrogenase and transient alopecia
Christiaens et al¹ Zalmanovicci et al² Gupta et al³
Design Randomised Systematic Review-21 open label RCT
placebo-controlled RCT studies
trial
Popula- 78 nonpregnant 916 outpatient, healthy 338 nonpregnant
tion women; AUC women; AUC women; AUC
Interven- Nitrofurantoin 100 Nitrofurantoin vs 5-day nitrofurantoin vs
tion mg vs placebo 4x/d cotri/beta lactam for ≥ 3-day TMP-SMX
x3 d 3days
Conclu- Nitrofurantoin > No significant difference No significant difference
sion placebo between nitrofurantoin between nitrofurantoin
Bacteriologic; and and TMPSMX/beta versus TMP-SMX in all
symptomatic cure by lactam for all outcomes outcomes measured
Day 3 and 7 measured
¹Christiaens T, et al. RCT of Nitrofurantoin vs placebo in treatment of AUC.
British Journal of General Practice, 2002
²Zalmanovici T, et al. Antimicrobial agents for treating UUTI in women. Cochrane review 2010
³Gupta K., et al. Short-Course Nitrofurantoin for AUC. Archives of Internal Medicine. 2007.
Which antibiotics are effective for acute
uncomplicated cystitis?
◦ Fosfomycin (3 g in a single dose) is also a
recommended antibiotic due to its high efficacy,
convenience of a single dose, low propensity for
collateral damage, good activity against
multidrug-resistant uropathogens, and minimal
adverse effects. However, there are no local
resistance data to date.
Strong recommendation
High quality of evidence
Which antibiotics are effective for acute
uncomplicated cystitis?
Pivmecillinam (400 mg BID for three to
seven days) can be used in areas where it is
available, as it has reasonable treatment
efficacy. However, it is not currently
available in the country. Local resistance
data is also absent.
Strong recommendation
High quality of evidence
Which antibiotics are effective for acute
uncomplicated cystitis?
Quinolones should NOT be used as a first
line drug despite their efficacy due to the
high propensity for collateral damage.
Strong recommendation
High quality of evidence
Which antibiotics are effective for acute
uncomplicated cystitis?
Beta-lactam agents, including amoxicillin-
clavulanate, cefaclor, cefdinir,
cefpodoxime-proxetil, ceftibuten, and
cefuroxime are appropriate choices for
therapy when other recommended agents
cannot be used.
Strong recommendation
High quality of evidence
What is the effective duration of treatment for acute
uncomplicated cystitis?
For acute uncomplicated cystitis, nitrofurantoin should
be given for 5 days¹, while fosfomycin is given as a
single dose².
For the alternative agents:
A 3-day course for fluoroquinolones is recommended³.
A 7-day regimen for beta-lactams (cefuroxime,
cefadroxil, cefpodoxime, cefixime, co-amoxyclav) is
recommended³.
Strong recommendation
High quality of evidence
¹Gupta K., et al. Short-Course Nitrofurantoin for AUC. Archives of Internal Medicine.2007.
²Falagas et al. Fosfomycin vs other antibiotics for AUC: meta-analysis. Journal of Antimicrobial Chemotherapy.2010.
³ Milo G et al. Duration of antibiotic for uncomplicated UTI. Cochrane 2009.
In elderly women (>65 years) with acute
uncomplicated cystitis, what is the
effective duration of treatment?
◦ In otherwise healthy elderly women with AUC,
the recommended duration of treatment is
the same as with the general population (See
Table 4).
Strong recommendation
High quality of evidence
Table 4. Antibiotics that can be used for acute
uncomplicated cystitis
Recommended dose
Antibiotics
and duration
Primary Nitrofurantoin 100 mg BID for 5
monohydrate/ days per orem (PO)
macrocrystal (NOT sold
locally)
Nitrofurantoin 100 mg QID for 5
macrocrystals days PO
Fosfomycin trometamol 3 g single dose PO
Table 4. Antibiotics that can be used for acute uncomplicated cystitis
Recommended dose
Antibiotics
and duration
Alternative Pivmecillinam (NOT sold 400 mg BID for 3–7 days PO
locally)
Ofloxacin 200mg BID for 3 days PO
Ciprofloxacin 250mg BID for 3 days PO
Ciprofloxacin extended release 500mg OD for 3 days PO
Levofloxacin 250mg OD for 3 days PO
Norfloxacin 400mg BID for 3 days PO
Amoxicillin-clavulanate 625mg BID for 7 days PO
Cefuroxime 250mg BID for 7 days PO
Cefaclor 500mg TID for 7 days PO
Cefixime 200mg BID for 7 days PO
Cefpodoxime proxetil 100mg BID for 7 days PO
Ceftibuten 200 mg BID for 7 days PO
ONLY if with Trimethoprim- 160/800 mg BID for 3 days PO
proven sulfamethoxazole (TMP-SMX)
susceptibility
What should be done for women whose
symptoms worsen, do not completely resolve,
or do not improve after completion of
treatment?
◦ Patients whose symptoms worsen or do not improve
after completion of treatment should have a urine
culture done, and, the antibiotic should be empirically
changed pending result of sensitivity testing.
◦ Patients whose symptoms fail to resolve after
treatment should be managed as complicated UTI.
Strong recommendation
Low quality of evidence
What is the clinical utility of a post-
treatment urine culture?
◦ Routine post-treatment urine culture and
urinalysis in patients whose symptoms have
completely resolved are NOT recommended
as it does not provide any added clinical
benefit.
Strong recommendation
Low quality of evidence
Healthy non-pregnant woman with
dysuria, frequency, urgency or hematuria
1
Treat empirically with recommended oral antibiotics
2
Reassess at end of therapy.
3 4
Symptoms YES No further
resolved? treatment.
5 NO
Do urinalysis, urine culture and change
antibiotics empirically pending urine c/s results.
Task Force Members of the CPG Update on UTI
Dr. Mediadora C. Saniel, Chair
Dr. Marissa M. Alejandria, Co-chair
Uncomplicated UTI Cluster
Thea C. Patino (Head)
Evalyn A. Roxas (Head)
Karen Marie R. Gregorio
Annabelle M. Laranjo
Kathryn U. Roa
Rommel P. Sumilong
Anna Marie S. Velasco
Rosally P. Zamora
