1 Treatment of Urinary Tract Infections

PROF. AZZA El-Medany

4 Classification of urinary tract infections 1- Symptomatic infections Uncomplicated UTI (mainly in women) acute cystitis Acute urethritis recurrent cystitis

5 Acute pyelonephritis Complicated UTI Acute and chronic prostatitis 2- Asymptomatic bacteriuria

Urinary tract infections(UTI’s) It is the 2 nd most common infection ( after RTI’s). It is often associated with some obstruction of the flow of urine. It is more common in women more than men Incidence of UTI increases in old age(10% of men & 20% of women).

Continue Normally urine is sterile. Bacteria comes from digestive tract to opening of the urethra. 7

What are the causes of UTI’s. Obstruction of the flow of urine (e.g. kidney stone) Enlargement of prostate gland in men (common cause) Catheters placed in urethra and bladder. Not drinking enough fluids. Waiting too long to urinate. Large uterus in pregnant women. Poor toilet habits(wiping back to front for women) Disorders that suppress the immune system(diabetes & cancer chemotherapy).

Organisms Causing urinary tract infections Gm negative bacteria (most common): E.coli (approx. 80% of cases) Proteus Klebsiella Pseudomonas Gm positive bacteria ( less common): Staphylococcus species Chlamydia trachomatis,Mycoplasma & N. gonorrhea

Treatment of uncomplicated and complicated UTI’s Antimicrobial agents:  TMP or TMP/SMX (co-trimoxazole)  Nitrofurantoin  Quinolones  Tetracyclines  Aminoglycosides

Continue β-Lactam antibiotics Extended spectrum penicillins Cephalosporins ( 3 rd G. ) 11

Sulfamethoxazole / Trimethoprim (SMX) (TMP) Co-trimoxazole ( Bactrim, Septra ) each agent alone is bacteriostatic Together they are bactericidal (synergism)

MECHANISM OF ACTION P-Aminobenzoic Acid Dihydropteroate Sulfonamides synthetase Dihydrofolate Dihydrofolate reductase Tetrahydrofolate Nucleic acid synthesis Trimethoprim

PHARMACOKINETICS Sulfonamides given orally Rapidly absorbed from stomach and small intestine. Widely distributed to tissues and body fluids & crossing the placenta. bind to serum protein. Metabolized in the liver by the process of acetylation. Eliminated in the urine, partly as such and partly as acetylated derivative.

Continue Trimethoprim ( TMP ) given orally Well absorbed from the gut Widely distributed in body fluids & tissues More lipid soluble than SMX Protein bound 60% of TMP or its metabolite is excreted in the urine TMP concentrates in the prostatic fluid.

Clinical uses Acute urinary tract infections Complicated urinary tract infections Recurrent urinary tract infections especially in females Prostatitis ( acute/ chronic )

ADVERSE EFFECTS  Gastrointestinal ( Nausea, vomiting)  Allergy  Hematologic 1) Acute hemolytic anemia a) hypersensitvity b) G6PD deficiency 2) Megaloblastic anemia due to TMP.  Kernicterus ( Jaundice due to Displace bilirubin )

CONTRAINDICATIONS  Pregnancy  Nursing mother  Infants under 6 weeks  Renal or hepatic failure  Blood disorders

Nitrofurantoin Effective against E. coli Gram positive cocci are susceptible Not effective against P- aeruginosa

Mechanism of action Changed by bacteria to an active agent that inhibits various enzymes and damages bacterial DNA 20

Pharmacokinetics Absorbed orally Well concentrated in the urine 75%of the dose is rapidly metabolized by the liver, 25% is excreted in the urine unchanged. Drug & its metabolites are excreted in the urine Turns urine to a dark orange- brown.

Continue Given with food Keep urinary pH below 5.5 ( acidic urine augment drug antibacterial activity ) 22

Adverse effects of nitrofurantoin  GIT disturbances: nausea, vomiting, diarrhea & gastric bleeding ( must be taken with food ).  Headache and nystagmus.  Hemolytic anemia  Pulmonary fibrosis ( on chronic use )

Contraindications  Patients with G 6PD deficiency  Neonates ( babies up to the age of one month )  Pregnant women ( after 38 weeks of pregnancy )

Therapeutic Uses Used as urinary antiseptics but has little or no systemic antibacterial effect. Its usefulness is limited to lower UTI’s. Dose: mg ( orally four times daily ) for 7 days

Tetracyclines Doxycycline Tetracycline

Tetracyclines Broad spectrum antibiotic Bacteriostatic Mechanism of action Inhibit protein synthesis by binding reversibly to 30 s ribosomal subunit

DOXYCYCLINE Pharmacokinetics Long acting tetracycline Usually given orally once daily Absorption is % Absorption in the upper s. intestine

Continue Absorption is impaired by  1- divalent cations ( Ca, Mg, Fe ) 2- milk and its products 3- antacids ( aluminium hydroxide gel, sodium bicarbonate)

Continue Protein binding % Distributed well, including prostatic tissues Cross placenta and excreted in milk Metabolized in liver Excreted through non renal route

Adverse effects  Nausea, vomiting, epigastric pain and diarrhea  Thrombophlebitis ( i.v route )  Hepatic toxicity ( prolonged therapy with high dose )  Brown discoloration & deformity of teeth ( children)  Deformity or growth inhibition of bones( children)  Vertigo  Superinfections & deformity of teeth ( children) Deformity

Therapeutic Uses  Treatment of UTI’s due to Mycoplasma & Chlamydia.  Prostatitis

Contraindications Pregnancy Breast feeding Children ( below 10 years ) 33

Aminoglycosides (Gentamicin ) Bactericidal antibiotics Inhibits protein synthesis by binding to 30S ribosomal subunits. Active against gram negative aerobic organisms. Poorly absorbed orally Given I.M, I.V., cross placenta

CONTINUE Excreted unchanged in urine More active in alkaline medium Adverse effects : Ototoxicity Nephrotoxicity Neuromuscular blocking effect

Therapeutic uses of Gentamicin Severe UTIs caused by gram negative aerobic organisms (pseudomonas ).

Contraindications Renal dysfunction Pregnancy Patients with hearing problem (Diminished (hearing Myasthenia gravis

( A) Extended- spectrum penicillins Amoxicillin / clavulanic acid piperacillin or piperacillin / tazobactam 38 β-Lactam antibiotics

Mechanism of actions Inhibit bacterial cell wall synthesis Bactericidal 39

Piperacillin Effective against pseudomonas aeruginosa & Enterobacter. Penicillinase sensitive Can be given in combination with β- lactamase inhibitors as clavulanic acid, sulbactam, tazobactam.

(B) 3 rd generation cephalosporins Ceftriaxone & Ceftazidime Mainly effective against gm negative bacteria. They are given parenterally Given in severe / complicated UTIs & acute prostatitis

Fluroquinolones Ciprofloxacin, levofloxacin Inhibits DNA gyrase enzyme

Clinical uses UTIs caused by multidrug resistance organisms as pseudomonas. Prostatitis

PROSTATITIS A ) Acute prostatitis: Non- catheter- or catheter associated usually due to gm- (E.coli or Klebsiella) b ) Chronic prostatitis due to E.coli, Klebsiella & Proteus

Antibiotics used for treatment of prostatitis TMP/SMX 3 rd Generation cephalosporins (ceftriaxone) Quinolones ( ciprofloxacin, levofloxacin ) Tetracyclines ( Doxycycline) 45