Pharmacology of

Urinary tract
infections
Dr Aigbepue Stephen
Urinary tract infections(UTI’s)
• It is the 2nd most common
• 1. Upper urinary tract (kidney infection ( after RTI’s).
&ureters) infections: pyelonephritis • It is often associated with some
obstruction of the flow of urine.
• Lower urinary tract (bladder, • It is more common in women
urethra & prostate): cystitis , more than men
urethritis & prostatitis. • 30:1 (Why?).
• Incidence of UTI increases in old
• ** Upper urinary tract infections age(10% of men & 20% of
are more serious. women).
What are the causes
of UTI’s
• Normally urine is sterile. Bacteria comes from • Bacteria responsible of urinary tract
digestive tract to opening of the urethra.
infections
• Obstruction of the flow of urine(e.g. kidney
• Gm- bacteria (most common):
stone)
• E.coli (approx. 80% of cases)
• Enlargement of prostate gland in men(common
cause) • Proteus
• Catheters placed in urethra and bladder. • Klebsiella
• Pseudomonas
• Not drinking enough fluids.
• Gm+ bacteria :
• Waiting too long to urinate.
• Staphylococcus Saprophyticus
• Large uterus in pregnant women.
• Poor toilet habits(wiping back to front for • Chlamydia trachomatis ,Mycoplasma & N.
women) gonorrhea
• Disorders that suppress the immune • (limited to urethra, unlike E.coli may be sexually
system(diabetes & cancer chemotherapy). transmitted)
Urinary tract infections can be:
• Simple: Non-catheter associated(community-acquired).
• Do not spread to other parts of the body and go away readily with
treatment ( Due to E.coli in most cases).
• Complicated: Catheter- associated(nosocomial) , immune-
suppression, stones, renal disease, diabetes)
• Spread to other parts of the body and resistant to many antibiotics
and more difficult to treat.{Due to hospital- acquired bacteria(E.coli,
Klebsiella,, Proteus, Pseudomonas, enterococci, staphylococci)}
Classification of drugs used for UTI
• Fluoroquinolones • Inhibitors of Folate reduction
• Ciprofloxacin • Pyrimethamine
• Delafloxacin • Trimethoprim
• Gemifloxacin
• Levofloxacin
• Combination of Inhibitors of
• Moxifloxacin folate synthesis and reduction
• Ofloxacin • Cotrimoxazole(trimethoprim +
sulfamethoxazole)
• Inhibitors of Folate Synthesis
• Mafenide • Urinary tract Antiseptics
• Silver sulfadiazine • Methenamine
• Sulfadiazine • Nitrofurantoin
• Sulfaslazine • Nalidixic acid
Fluoroquinolones
Resistance
Mechanism of action • Numerous mechanisms of fluoroquinolone resistance exist
in clinical pathogens. High-level fluoroquinolone resistance
• Most bacterial species maintain two distinct type is primarily driven by chromosomal mutations within
II topoisomerases that assist with topoisomerases, although decreased entry, efflux systems,
deoxyribonucleic acid (DNA) replication, DNA and modifying enzymes play a role. Mechanisms
gyrase, and topoisomerase IV. DNA gyrase is responsible for resistance include the following:
responsible for reducing torsional stress ahead of 1. Altered target binding
replicating forks by breaking double-strand DNA • Mutations in bacterial genes encoding DNA gyrase or
and introducing negative supercoils. topoisomerase IV (for example, gyrA or parC) alter target
site structure and reduce binding efficiency of
fluoroquinolones.
• Topoisomerase IV assists in separating daughter
chromosomes once replication is completed. 2. Decreased accumulation
Following cell wall entry through porin channels, • Reduced intracellular concentration is linked to
fluoroquinolones bind to these enzymes and 1) a reduction in membrane permeability or
interfere with DNA ligation. 2) efflux pumps.
• Alterations in membrane permeability are mediated
through a reduction in outer membrane porin proteins, thus
• This interference increases the number of limiting drug access to topoisomerases. Efflux pumps
permanent chromosomal breaks, triggering cell actively remove fluoroquinolones from the cell.
lysis. In general, fluoroquinolones have different
targets for gramnegative (DNA gyrase) and gram- 3. Fluoroquinolone degradation
positive organisms (topoisomerase IV), resulting • An aminoglycoside acetyltransferase variant can acetylate
in rapid cell death fluoroquinolones, rendering them inactive.
Fluoroquinolones Spetrum of Activities
Pharmacokinetics 2. Distribution
• Binding to plasma proteins ranges from 20% to 84%.
1. Absorption Fluoroquinolones distribute well into all tissues and body
fluids.
• Fluoroquinolones are well absorbed • Concentrations are high in bone, urine (except
after oral administration, with moxifloxacin), kidney, prostatic tissue (but not prostatic
levofloxacin and moxifloxacin having a fluid), and lungs as compared to serum.
• Penetration into cerebrospinal fluid is good, and these
bioavailability that exceeds 90% (Figure agents may be considered in certain central nervous
31.3). system (CNS) infections.
• Ingestion of fluoroquinolones with • Accumulation in macrophages and polymorphonuclear
leukocytes results in activity against intracellular
sucralfate, aluminum- or magnesium- organisms such as Listeria, Chlamydia, and
containing antacids, or dietary Mycobacterium.
supplements containing iron or zinc can 3. Elimination
reduce the absorption. • Most fluoroquinolones are excreted renaly. Therefore,
• Calcium and other divalent cations also dosage adjustments are needed in renal dysfunction.
• Moxifloxacin is metabolized primarily by the liver, and
interfere with the absorption of these while there is some renal excretion, no dose adjustment is
agents required for renal impairment.
 Adverse reactions
• In general, fluoroquinolones are well tolerated
• Common adverse effects leading to discontinuation are; nausea, vomiting, headache, and dizziness.
• These agents carry boxed warnings for tendinitis, tendon rupture, peripheral neuropathy, and CNS
effects (hallucinations, anxiety, insomnia, confusion, and seizures).
• Patients taking fluoroquinolones are at risk for phototoxicity resulting in exaggerated sunburn reactions.
• Patients should use sunscreen and avoid excessive exposure to ultraviolet (UV) light. Arthropathy is
uncommon, but arthralgia and arthritis are reported with fluoroquinolone use in pediatric patients.
• Use in the pediatric population should be limited to distinct clinical scenarios (for example, cystic
fibrosis exacerbation).
• Hepatotoxicity or blood glucose disturbances (usually in diabetic patients receiving oral hypoglycemic
agents or insulin) have been observed.
• Identification of any of these events should result in prompt removal of the agent. Fluoroquinolones
may prolong the QT interval, and these agents should be avoided in patients predisposed to arrhythmias
c

or taking medication associated with QT prolongation.

• Ciprofloxacin inhibits P450 1A2- and 3A4-mediated metabolism. Serum concentrations of
medications such as theophylline, tizanidine, warfarin, ropinirole, duloxetine, caffeine,
sildenafil, and zolpidem may be increased
 Examples of clinically useful fluoroquinolones
• Due to increasing resistance and boxed warnings, • 3. Moxifloxacin
fluoroquinolones should be used with caution in select
• Moxifloxacin has enhanced activity against gram-positive
circumstances. They may be considered in patients who do not
tolerate other agents (for example, severe beta-lactam allergies) organisms (for example, S. pneumoniae), gram-negative
or as definitive therapy once susceptibilities are available. anaerobes, and Mycobacterium spp.
Listed below are potential indications for these agents. • The drug may be used for CAP, but not hospitalacquired
pneumonia due to poor coverage of P. aeruginosa. It may be
• 1. Ciprofloxacin considered for mild-to-moderate intraabdominal infections, but
• Ciprofloxacin has good activity against gram-negative should be avoided if patients have fluoroquinolone exposure
bacilli, including P. aeruginosa. within previous three months, due to increasing B. fragilis
• Ciprofloxacin is used in the treatment of traveler’s diarrhea, resistance. Moxifloxacin may be considered as a second-line
typhoid fever, and anthrax. It is a second-line agent for agent for management of drug-susceptible tuberculosis.
infections arising from intra-abdominal, lung, skin, or urine • 4. Gemifloxacin
sources.
• Gemifloxacin is indicated for management of community-
• Of note, high-dose therapy should be employed when treating acquired respiratory infections.
Pseudomonas infections.
• Unlike the other compounds, it is only available as an oral
• 2. Levofloxacin formulation.
• Levofloxacin [leev-oh-FLOX-a-sin] has similar activity to • 5. Delafloxacin
ciprofloxacin and they are often interchanged when
• Delafloxacin has improved activity against gram-positive
managing gram-negative bacilli, including P. aeruginosa.
cocci, including MRSA and Enterococcus spp. Due to its
Levofloxacin has enhanced activity against S. pneumonia and
spectrum of activity, it is an option for managing acute bacterial
is first-line therapy for community-acquired pneumonia (CAP).
skin and skin structure infections. It is available as an
• It is a second-line agent for the treatment of S. maltophilia. intravenous and oral formulation.
(Folate Antagonists/ Combination)
Sulfamethoxazole (SMX)-Trimethoprim(TMP)
• Antibacterial spectrum
Co-trimoxazole
• SMX: Sulfa drugs have in vitro activity against
Alone, each agent is gram-negative and gram-positive organisms.
Common organisms include
bacteriostatic Enterobacteriaceae, Haemophilus influenzae,
Streptococcus spp., Staphylococcus spp., and
Together they are Nocardia. Additionally, sulfadiazine in
combination with the dihydrofolate reductase
bactericidals(synergism) inhibitor pyrimethamine is the preferred
The optimal ratio of TMP to SMX treatment for toxoplasmosis.

in vivo is 1:20 • TMP: The antibacterial spectrum of

(formulated 5(SMX):1(TMP); 800mg trimethoprim is similar to that of
sulfamethoxazole. However, trimethoprim is 20-
SMX+160mg TMP; 400 mg SMX+ to 50-fold more potent than the sulfonamides.
80 mg TMP; 40 mg SMX+8 mg • Trimethoprim may be used alone in the
TMP). treatment of urinary tract infections (UTIs) and
in the treatment of bacterial prostatitis
(although fluoroquinolones and cotrimoxazole
 MECHANISM OF ACTION
P-Aminobenzoic Acid

Dihydropteroate Sulfonamides
synthetase
Dihydrofolate

Dihydrofolate Trimethoprim
reductase

Tetrahydrofolate

Nucleic acid synthesis

 Pharmacokinetics
Sulfonamides Trimehoprim ( TMP )
• Mainly given orally
• Rapidly absorbed from stomach and Usually given orally, alone or in
small intestine. combination with SMX
• Widely distributed to tissues and body Well absorbed from the gut
fluids ( including CNS, CSF ), placenta Widely distributed in body fluids & tissues
and fetus. ( including CSF )
• Absorbed sulfonamides bind to serum
More lipid soluble than SMX
protein( approx. 70% ).
• Metabolized in the liver by the process Protein bound ( approx.40 % )
of acetylation. 60% of TMP or its metabolite is excreted
• Eliminated in the urine, partly as such in the urine
and partly as acetylated derivative. TMP concentrates in the prostatic fluid.
Adverse effects: Resistance
• Gastrointestinal- Nausea, vomiting
• Allergy • SMX: Bacteria that obtain folate from their
• Crytalluria(sulphonamides) environment are naturally resistant to sulfa drugs.
• Hematologic • Acquired bacterial resistance to the sulfa drugs can
a) Acute hemolytic anemia(sulphonamides) arise from plasmid transfers or random mutations.
a) hypersensitvity b) G6PD deficiency
Resistance may be due to
b) Megaloblastic anemia due to TMP.
• Drug interactions 1) Altered dihydropteroate synthetase,
Displace bilirubin- if severe – 2) Decreased cellular permeability to sulfa drugs, or
kernicterus(sulphonamodes)
Potentiate warfarin, oral hypoglycemics. 3) Enhanced production of the natural substrate,
PABA. [Note: Organisms resistant to one member
Contraindication of this drug family are resistant to all.]
• Pregnancy • TMP: Resistance in gram-negative bacteria is due
to the presence of an altered dihydrofolate
• Nursing mother
reductase that has a lower affinity for
• Infants under 6 weeks trimethoprim.
• Renal or hepatic failure from • Efflux pumps and decreased permeability to the
• Blood disorder drug may play a role.
Antiseptics
Nitofurantoin Pharmacokinetics
• Antibacterial Spectrum: • Absorption is complete after oral
Effective against E. coli or Staph. use
saprophyticus , but other • Metabolized (75%)& excreted so
common UT gm- bacteria may rapidly that no systemic
be resistant. antibacterial action is achieved.
• Mechanism of Action: Sensitive • Concentrated in the urine(25% of
bacteria reduce the drug to an the dose excreted unchanged)
active agent that inhibits various • Urinary pH is kept <5.5(acidic) to
enzymes and damages DNA. enhance drug activity.
• It turns urine to a dark orange-
brown.
Adverse Effects of Nitrofurantoin Therapeutic Uses of
• GI disturbances: bleeding of the Nitrofurantoin
stomach,nausea, vomiting and
diarrhea(must be taken with food). It is used as urinary antiseptics .
• Pulmonary fibrosis. Its usefulness is limited to lower
• Headache and nystagmus. UTI’s & cannot be used for
upper UT or systemic infections.
• Containdications:
• Dose: 50-100 mg, po q 6h/7
• Pts with G6PD deficiency(haemolytic
anaemia)
days.
• Neonates • Long acting: 100mg twice daily.
• Pregnant women(after 38 wks of pregnancy)
Methenamine
• 1. Mechanism of action • Antibacterial
• Methenamine salts are spectrum
hydrolyzed to ammonia and • Methenamine is primarily used for
formaldehyde in acidic urine chronic suppressive therapy to reduce
(pH ≤ 5.5). the frequency of UTIs.
• Formaldehyde denatures • Methenamine is active against E.
proteins and nucleic acids, coli, Enterococcus spp., and
Staphylococcus spp. It has some
resulting in bacterial cell death. activity against Proteus spp. And
• Methenamine is combined Pseudomonas aeruginosa, but urine pH
with a weak acid (for example, must be kept acidic to achieve
bactericidal activity.
hippuric acid) to maintain urine
• The main benefit of methenamine
acidity and promote production
is the lack of selection for resistant
of formaldehyde organisms.
Methenamine
• Pharmacokinetics
• Methenamine is orally absorbed, with up to 30%
decomposing in gastric juices, unless protected by
enteric coating.
• It reaches the urine through tubular secretion and
glomerular filtration. Concentrations are sufficient to
treat susceptible organisms.
• Due to ammonia formation, use should be avoided in
hepatic insufficiency.
• 4. Adverse effects
• The major adverse effect of methenamine is
gastrointestinal distress, although at higher doses,
albuminuria, hematuria, and rashes may develop.
• Methenamine mandelate is contraindicated in
patients with renal insufficiency, because mandelic acid
may precipitate.
• The methenamine hippurate formulation should
be used instead. [Note: Sulfonamides, such as
cotrimoxazole, react with formaldehyde and must
not be used concomitantly with methenamine. The
combination increases the risk of crystalluria and
mutual antagonism.]
 Nalidixic Acid
• Non fluorinated quinolone Adverse drug reaction:
• Its bacteriocidal • Infrequent: GI upset, rashes
Mechanism of Action • Headaches, drowsiness, vertigo,
• Inhibits the replication of bacteria by visual disturbances
interfering with the action of DNA • Seizure in children
gyrase during bacterial growth and • Nausea and vomiting
development.
• Abdominal pain
• Resistance develop rather rapidly
• Photosensitivity, urticarial amd
Uses: fever
• Second line drug for UTI • Contraindicated in infants
• Recurrent cases
• On the basis of sensitivity reports
 Adjuvant Antibiotics
Doxycyclin Side effects
• It is a long acting tetracycline 1. nausea, vomiting ,diarrhea & epigastric pain(give with
food)
Mechanism of action 2. Thrombophlebitis – i.v
• Inhibit protein synthesis by binding reversibly 3. Hepatic toxicity ( prolonged therapy with high dose )
to 30 s subunit 4. Brown discolouration of teeth – children
Pharmacokinetics 5. Deformity or growth inhibition of bones – children
• Usually given orally 6. Vertigo
• Absorption is 90-100% 7. Superinfections.
• Absorbed in the upper s. intestine & best in
absence of food Contraindication
• Pregnancy
• Food & di & tri-valent cations ( Ca, Mg, Fe, AL)
impair absorption • Breast feeding
• Children(below 10 yrs)
• Protein binding 40-80 %
Therapeutic Uses
• Distributed well, including CSF • Treatment of UTI’s due to Mycoplasma & Chlamydia,
• Cross placenta and excreted in milk 100 mg p.o bid for 7 days.
• Largely metabolized in the liver • Prostatitis
Aminoglycosides: B-Lactam Antibiotics
e.g. GENTAMICIN. • Extended- spectrum penicillins
• Bactericidal antibiotics (e.g.piperacillin)
• Inhibits protein synthesis by binding to 30S • Cephalosporins
ribosomal subunits. Piperacillin:
• Active against gram negative aerobic organisms. • Effective against pseudomonas aeruginosa &
• Poorly absorbed orally(highly charged). Enterobacter.
• Penicillinase sensitive
• cross placenta.
• Can be given in combination with β-lactamase
• Excreted unchanged in urine inhibitors as clavulanic acid ,sulbactam,
• More active in alkaline medium tazobactam.
Adverse effects : 3rd Generation Cephalosporin:
• Ototoxicity Ceftriaxone & Ceftazidime
• Nephrotoxicity • Mainly effective against gm- bacteria.
• Acts by inhibition of cell wall synthesis
• Neuromuscular blocking effect
Bactericidal
Therapeutic uses of Gentamicin in UTI’s
• They are given parenterally
• Severe infections caused by gram negative
organisms (pseudomonas or enterobacter). • Given in severe / complicated UTIs
Reference
• Lippincot’s Illustrated Reviews : Pharmacology 7th and 5th Edition
• Bertram Katzung, Susan Masters, Anthony Trevor-Basic and Clinical
Pharmacology, 11th Edition (LA
• The Internet
• Thank you for Listening