PRINCIPLES IN THE

PHARMACOLOGICAL TREATMENT
OF URINARY TRACT INFECTION

LECTURE 1

VIJAYA LECHIMI RAJ

Learning Outcomes
On completing this lecture, you should be able to:
Explain what is significant bacteruria and list the
common pathogens causing UTI
Explain the general principles in the treatment of UTI:
Acute cases
Chronic cases
Dose
pH of urine
Fluid intake
Classify drugs used in the treatment of UTI
Describe what are urinary antiseptics
Explain conditions when antibacterial prophylaxis is
indicated
CONTENTS
Bacteruria
General principles in the treatment of UTI
Classification of drugs used in UTI
Bacteriostatic drugs – sulfonamides, tetracycline,
nitrofurantoin
Bactericidal drugs – cotrimoxazole, ampicillin,
extended spectrum penicillins, fluoroquinolones and
cephalosporins
Urinary antiseptics
Antibacterial prophylaxis
Following instrumentation of the urinary tract, chronic
prostatitis and pregnant women with asymptomatic
bacteruria
Bacteriuria
The presence of bacteria in the urine.
The presence of more than 100,000 pathogenic
bacteria/mL of urine is usually considered significant
and diagnostic of UTI.
Bacteriuria may be asymptomatic.
UTI is commonly an isolated, never (or rarely) repeated
event
At least 50% of women will experience it at some point
in their lives.
Rarely result in significant kidney damage
A concern when there is relapse or recurrent (re-
infection)
Bacteriuria
RELAPSE:
Recurrence of bacteriuria with the same organism within
7 days of treatment
Implies failure to eradicate infection
Conditions: stones, bacterial prostatitis, scarred kidneys,
polycystic disease
REINFECTION:
Absent after treatment for at least 14 days followed by
recurrence with the same or different organism
Not due to failure to eradicate infection
Result of reinvasion of a susceptible tract with new
organisms
80% of recurrent infections are due to reinfection
Bacteriuria
Common pathogens causing UTI include
Gram-negative bacilli:
Escherichia coli
 Most common, causing bout 80% of uncomplicated
upper and lower UTI
Staphylococcus saprophyticus
 Second most common

Klebsiella sp
 Common is Klebsiella pneumoniae

Proteus mirabilis
Occasionally : Enterobacter
Recurrent infections: Serratia and Pseudomonas
 General Principles in the treatment of UTI
1. Acute cases:
 Majority involve only 1 organism – E. coli
 Largely self limiting
 High urine flow rates with frequent bladder voiding
may suffice
 Many single dose therapies are successful but
normally 3 day regimen for lower UTI
 Upper UTIs require more aggressive and longer
treatment
 In either case – not more than 2 weeks regimen
 Advisable to choose a drug that does not disrupt
normal gut and perineal flora.
 General Principles in the treatment of UTI
2. Chronic cases:
 Chronic and recurrent (re-infection) may involve mixed
infections
 Usually due to E. coli, Klebsiella, Proteus, Serratia,
Pseudomonas, enterococci, and staphylococci
 Many isolates exhibit antibiotic resistance.
 Empirical antibiotic therapy ideally provides broad-
spectrum coverage against these pathogens
 If recurrence is frequent, chronic suppressive
treatment with cotrimoxazole, nitrofurantoin,
methenamine, cephalexin or norfloxacin may be given
 General Principles in the treatment of UTI
3. Dose:
 Acute cases – can be treated with single dose but the
preferred is a 3-day course
 Chronic cases – up to 2 weeks
 Prophylatic treatment – can take low doses of certain
antibiotics up to 6 months
 General concern is the development of resistance
 General Principles in the treatment of UTI
4. pH of urine:
 Certain drugs act better in acidic urine and others in
alkaline
 Seldom need to acidify or alkalinize urine as most
drugs for UTI attain high concentrations in urine
 In complicated cases or inadequate response,
measurement of urinary pH and appropriate corrective
measure may help
 In case of urease positive Proteus
 They split urea present in urine to NH
3
 Impossible to acidify urine
 Use drugs which act better at higher pH
 Favourable urinary pH for antimicrobial action
Acidic Alkaline pH immaterial
Nitrofurantoin Cotrimoxazole Chloramphenicol
Methenamine Aminoglycosides Ampicillin
Tetracycline (e.g. Gentamicin, Colistin
Cloxacillin etc)
Cephalosporins
Fluoroquinolones
 General Principles in the treatment of UTI
5. Fluid intake:
 Encouraged to drink a lot of water and frequent
urination – whenever feel like it and do not resist the
urge
 A water diuresis serves to 'flush' the urinary tract of
infecting organisms, and frequent voiding reduces
bacterial multiplication in the bladder
 In addition, a reduction in bacterial counts in the urine
by hydration would enhance the effect of factors
otherwise overwhelmed by large numbers of bacteria
(eg, bladder mucosal defences or the effect of
relatively low concentrations of antimicrobial drugs)
Classify drugs used in the treatment of UTI
1. Bacteriostatic drugs:
 Arrest the growth and
replication of bacteria
 Limits the spread of
infection while the
body’s immune
system attacks,
immobilizes and
eliminates pathogens
 e.g. sulfonamides,
tetracyclines,
nitrofurantoin
Classify drugs used in the treatment of UTI
2.Bactericidal drugs:
 Kill bacteria at drug serum levels achievable in
the patient
 Thus the total number of viable organisms
decreases
 It is possible for an antibiotic to be bacteriostatic
for one organism and bactericidal for another
 e.g. cotrimoxazole, ampicillin, extended spectrum
penicillins, fluoroquinolones and cephalosporins
Classify drugs used in the treatment of UTI
1. Sulphonamides:
  dependability in acute UTI – not used as single drug
 May be used for suppressive and prophylactic therapy
 Active against selected enterobacteria in the urinary
tract and nocardia
 Bacteriostatic
Mechanism:
 Dihydrofolic acid is synthesized from p-aminobenzoic
acid (PABA), pteridine and glutamate
 Sulphonamides are synthetic analogs of PABA
 Compete for the bacterial enzyme, dihydropteroate
synthetase
 Thus inhibit the synthesis of bacterial dihydrofolic acid
and the formation of essential cofactors
<back>
Adverse effects:
 Crystalluria
 Nephrotoxicity develops as a result crystalluria
 Adequate hydration and alkalinization
 Hypersensitivity
 rashes, angioedema and Steven-Johnson syndrome are fairly
common
 Hemopoetic disturbances
 Hemolytic anemia in G6PD, granulocytopenia,
thrombocytopenia can occur
 Kernicterus
 Can displace bilirubin from binding sites on serum albumin

 Drug potentiation – warfarin and methotrexate

 Contraindications
 Pregnant women, newborn and infants under 2 months
Classify drugs used in the treatment of UTI
2. Cotrimoxazole:
 Combination of trimethoprim and sulfamethoxazole
 Response rate and use have 
 May be used empirically in acute UTI without
bacteriological data
 Majority of urinary pathogens including C.
trachomatis are covered
 Should not be used in pregnancy
Mechanism:
 Synergic effect of inhibition of 2 sequential steps in
the synthesis of tetrahydrofolic acid <diag>
Adverse effects:
 Dermatologic
 Very common and can be severe in the elderly
 GI - Nausea, vomiting , glossitis and stomatitis
 Hematologic
 Megaloblastic anemia, leukopenia and
thrombocytopenia – can be reversed by concurrent
administration of folinic acid
 Hemolytic anemia in G6PD patients
 HIV patients – drug-induced fever, rashes, diarrhea
and/or pancytopenia
 Drug interactions:
 Warfarin – prolonged prothrombin time
 Phenytoin – half life increased
 Methotrexate levels increased due to displacement
Classify drugs used in the treatment of UTI
3. Tetracyclines:
 Consist of 4 fused rings with a system of conjugated
double bonds
 Seldom effective now – most urinary pathogens are
resistant
 Broad spectrum – used only on basis of sensitivity
report and in C. trachomatis cystitis
 Bacteriostatic
Mechanism:
 Enters into susceptible organisms by passive
diffusion and by energy-dependent transport
 Binds irreversibly to the 30S subunit of the bacterial
ribosome and blocks access of amino acyl-tRNA to
the mRNA-ribosome complex at the acceptor site
 Bacterial protein synthesis is inhibited
Adverse effects:
 Gastric discomfort
 epigastric distress due to gastric mucosa irritation (take with
food except dairy products)
 Effects on calcified tissues
 Discoloration and hypoplasia of the teeth and a
temporary stunting of growth in children
 Fatal hepatotoxicity
 In pregnant women esp if experiencing pyelonephritis
 Phototoxicity – severe sunburn
 Vestibular problems – dizziness, nausea, vomiting
 Pseudotumor cerebri – rare- headache and blurred vision
 Superinfections
 Overgrowths of Candida (vagina), resistant Staph
(intestine), Clostridium difficile (pseudomembranous
colitis)
Classify drugs used in the treatment of UTI
4.Extended spectrum penicillin:
 Ampicillin and amoxicillin have an antibacterial
spectrum similar to that of penicillin G but are more
effective against gram-negative bacilli – extended
spectrum
 Resistance is a major clinical problem
 Inactivation by plasmid-mediated penicillinase
 Formulation with a β-lactamase inhibitor such as
clavulanic acid or sulbactam protects from
enzymatic hydrolysis and extends their
antimicrobial spectrum
 Amoxicillin + clavulanic acid
 Ampicillin + sulbactam
Mechanism
 Interferes with the last step of bacterial cell wall
synthesis (transpeptidation or cross-linkage)
 Resulting in exposure of the osmotically less sable
membrane
 Cell lysis can then occur either thru osmostic
pressure or activation of autolysins
 Bactericidal
 Only effective against rapidly growing organisms that
synthesize a peptidoglycan cell wall
 Process:
 Penicillin-binding proteins
 Inhibition of transpeptidase
 Production of autolysins
 Penicillin-binding proteins
 Bacterial enzymes involved in cell wall synthesis and
maintenance of morphological features
 Penicillin prevents cell wall synthesis and cause
morphological changes or lysis of susceptible bacteria
 Inhibition of transpeptidase
 Some PBP catalyze formation of cross-linkages between
peptidoglycan chains
 Inhibits this transpeptidase-catalyzed reaction
 Hinders formation of cross-links essential for cell wall
integrity
 Production of autolysins
 Bacteria produc degradative enzymes (autolysins) that
participate in the normal remodeling of cell wall
 In presence of penicillin, autolysins proceed in the
absence of cell wall synthesis
 Results in destruction of existing cell wall
Adverse effects
 Hypersensitivity
 Most important – rash, angioedema, anaphylaxis
 Its metabolite, penicilloic acid, serves as a hapten to cause
an immune response
 Diarrhea
 Caused by disruption of normal balance of intestinal
organism – common problem
 Nephritis – all have the potential
 Neurotoxicity
 Irritating to neuronal tissue and can provoke seizures if
injected intrathecally or if very high blood levels
 Special concern - epileptics
 Hematologic toxicities – decreased coagulation
 Cation toxicity
 Administered as Na or K salts
 Avoid by using potent drugs – low volume
Classify drugs used in the treatment of UTI
5.Ampicillin:
 In the past – drug of choice for initial treatment of
acute infections without bacteriological data
 But high failure and relapse rates has made it
unreliable for empirical therapy
 Many E. coli strains are now ampicillin-resistant
Classify drugs used in the treatment of UTI
6. Fluoroquinolones:
 E.g. Ciprofloxacin
 Highly effective and currently most popular drugs
 Potent against gram-negative bacilli and low cost
 To preserve efficacy, use should be restricted
 Valuable in complicated case – those with prostatitis,
indwelling catheter ad resistant to
cotrimoxazole/ampicillin
 Should not be given to pregnant women
Ciprofloxacin:
 Most frequently used
 Particularly useful for gram-negative organisms,
anthrax and infections associated with cystic fibrosis
Mechanism:
 Enter bacterium by passive diffusion thru water-filled
protein channels (porins) in the outer membrane
 Inhibit the replication of bacterial DNA by interfering with
the action of DNA gyrase (topoisomerase II) and
topoisomerase IV during bacteria growth and reproduction
 Binding to both gyrase and DNA forms a tertiary complex
that inhibits the resealing step
 Cause cell death by inducing cleavage of DNA
 Bacteriospecific – cross-resistance is rare but increasing
due to multidrug-resistant organisms
 Topoisomerase IV – required by bacteria for cell division
and implicated in segregating newly replicated DNA
 Also blocks this enzyme
 Inhibition of DNA gyrase more important in gram-negative
organisms
Adverse effects: Generally well tolerated
 GI – nausea, vomiting and diarrhea in 3-6% of patients
 CNS
 Headache and dizziness or light-headedness
 Patients with CNS disorders should be treated with
caution
 Phototoxicity
 Need to avoid excessive sunlight and apply sunscreen
(may not be sufficient)
 Connective tissue problems
 Avoid in pregnancy, nursing mother and children under
18 as can cause articular cartilage erosion (arthropathy)
 In adults above 60 can cause tendon rupture (tendonitis)
 Contraindications
 May prolong QTc interval – C/I in arrhythmias or those
taking antiarrhythmic drugs
Classify drugs used in the treatment of UTI
7.Cephalosporins:
 E.g. cefuroxime
 Β-lactam antibiotics closely related structurally and
functionally to penicillin
 Use is increasing, esp in women with nosocomial
Klebsiella and Proteus infections
 Used on the basis of sensitivity report but empirical
use for community acquired infection is also common
 Recommended as alternative drugs
 Mechanism similar to penicillin
 Adverse effects – allergic manifestation
 Those with anaphylactic reaction to penicillin – C/I
 Use with caution in those allergic to penicillin
Urinary antiseptics
 These drugs orally do not achieve antibacterial
levels in the circulation but are concentrated in the
kidney tubules and urine
 Have little or no systemic antibacterial effect
 Microorganisms at that site can be effectively
eradicated
 Effective for lower urinary tract infection
 E.g. – methenamine, nitrofurantoin and nalidixic
acid
Urinary antiseptics
Nitrofurantoin
 Less commonly used because of narrow antimicrobial
spectrum and its toxicity
 Sensitive bacteria reduce the drug to active metabolites
 The active metabolites will inhibit various enzymes and
damage bacterial DNA
 Activity is greater in acidic urine
 Drug is bacteriostatic
 Useful against E. coli but other common urinary tract
gram-negative bacteria may be resistant
 Gram-positive cocci are susceptible
 Adverse effects include gastrointestinal disturbances,
acute pneumonitis and neurologic problems
Antibacterial Prophylaxis
1. Instrumentation of the urinary tract:
 E.g. indwelling catheter
 Colonization of bladder is common after catheterization for
more than a few days
 To prevent development of antibiotic resistance, treatment is
recommended only of patient has symptoms or evidence of
systemic infection
 Treatment can be given prior to catheter removal as catheter-
introduced infections are slow to clear spontaneously
 Common infection – Candida sp
 Treatment is for those with evidence of invasive infection,
immunosuppressed
 how – remove/replace catheter and intravesical antifungals
Antibacterial Prophylaxis
2. Chronic prostatitis:
 Relapsing infection that is difficult to treat
 Presents as perineal pain, recurrent epididymo-
orchitis and prostatic tenderness with pus in
expressed prostatic secretion
 Drugs must be able to penetrate the prostate
 Tetracycline, ciprofloxacin (fluoroquinolones) and
cotrimaxozole
 for 4-6 weeks
 Long-term low-dose treatment may be required
Antibacterial Prophylaxis
3. Pregnant women:
 The urine of pregnant women should be cultured
as 2-6% have asymptomatic bacteriuria
 Must be treated and shown to be eradicated as
serious complication can occur
 Reinfection may require prophylactic therapy
 Tetracycline drugs should be avoided in
pregnancy
 Cotrimaxozole should be avoided in the first
trimester and sulphonamides in the third