pharmacotherapy of Uti

1. PHARMACOTHERAPY OF URINARY
TRACT INFECTION (UTI) &
CHLORAMPHENICOL &
TETRACYCLINES
Dr Viraj Shinde
Jr II
Dept. of Pharmacology,
GMCH, Nagpur

2. OVERVIEW
Introduction
Epidemiology
Pathogenesis
Definition
Drug therapy for UTI
Chloramphenicol
Tetracyclines

3. INTRODUCTION
 Common disorder
 Normal urinary tract is generally resistant to
infection.
 Female urinary tract is more susceptible to
infection.

4. CONTD..
 50% of patients, a predisposing cause cannot be
demonstrated.
 In recurrent UTI, it is essential to look for
predisposing causes.
 UTI may present itself as
 Acute infection
 Chronic infection

5. ACUTE INFECTION
 Two general anatomical categories
1. Lower tract infection : uretheritis and cystitis
2. Upper tract infection : Acute pyelonephritis,
prostatitis, intrarenal and perirenal abscesses.

6. CONTD..
Lower UTI Upper UTI
Increased frequency and urgency
of micturation, dysuria and pain in
the perineum
Loin pain, fever, chills and
leucocytosis.
Fever ,chills and leucocytosis are
generally absent.
Urine with pus cells, urine culture
is positive and shows significant
bacteriuria.
Infection is considered superficial
or mucosal infection
Infection is tissue invasion.

7. CHRONIC INFECTION
 Polyuria and nocturnal frequency may be present.
 General loss of health and weight, anaemia and
hypertension are also present
 Chronic pyelonephritis is an important cause of
hypertension and chronic renal failure.

8. EPIDEMIOLOGY
 Subdivided into catheter-associated (nosocomial)
and non catheter-associated (community acquired)
infection.
 Acute community acquired UTIs are very common.
 In women
 In 1-3% of school girls
 Then increased markedly with onset of sexual activity.

9. CONTD..
 In men
 First year of life
 Unusual under 50 year age.
 Asymptomatic bacteriuria is 50% but uncommon
among men under 50 year and common among
women in 20-50 year age group.
 Asympatomatic bacteriuria is more common among
elderly men and women with rates as high as 40-
50% in some studies.

10. ETIOLOGY
Gram negative (95%) Gram positive (5%)
E. coli (80%) Enterococci
Proteus Streptococci
Klebsiella Staphylococci
Aerobacter
Pseudomonas

11. PATHOGENESIS AND SOURCES OF INFECTION

12. CONDITIONS AFFECTING THE PATHOGENESIS
 Gender and sexual activity
 Pregnancy
 Obstruction
 Neurogenic bladder dysfunction
 Vesicoureteral reflux
 Bacterial virulence factors

13. CATHETER ASSOCIATED UTIS
 Bacteriuria develops in 10-15% of hospitalised
patients with short term indwelling urethral
catheters.
 Risk of infection is 3-5% per day of catheterization
 E.coli, proteus, pseudomonas, klebsiella, serratia,
staphylococci, enterococci and candida usually
cause these infection.

14. CONTD..
 Infection occurs when bacteria reach the bladder by
one of two routes
1. Migration through the column of urine in the
catheter lumen( intraluminal route)
2. Up the mucous sheath outside the
catheter(periuretheral route)

15. CONTD..
 Clinically catheter-associated infection usually
causes symptoms without fever
 Often resolve after withdrawal of the catheter

16. CONTD..
 In patients catheterized for <2 weeks, catheter-
associated UTIs can be prevented by use
 Of a sterile closed collecting system
 Aseptic technique
 Short course of systemic antimicrobial therapy
 Application of periuretheral antimicrobial ointments

17. DEFINITIONS
 Significant bacteriuria
 Colony count > 105 /ml of single species in a midstream
clean catch sample.
 Asymptomatic bacteriuria
 Significant bacteriuria in absence of symptoms of urinary
tract infection

18. CONTD..
 Simple UTI
 UTI with low grade fever, dysuria, frequency and
urgency and absence of symptoms of complicated UTI.
 Complicated UTI
 Presence of fever>39ºc, systemic toxicity, persistent
vomiting, dehydration, renal angle tenderness and
raised creatinine
 Recurrent infection
 Second episode of UTI

19. DIAGNOSIS
 Clinical features and history
 Microscopic examination of urine
 Dipstick tests
 Culture and sensitivity

20. BACTERIAL COUNTS ARE CLINICALLY RELEVANT IN A
SAMPLE OF MID STREAM URINE (MSU)IF:
 > 103 CFUs/mL in acute uncomplicated cystitis in a
woman
 > 104 CFUs/mL in acute uncomplicated
pyelonephritis in a woman
 > 105 CFUs/mL, or > 104 CFUs/mL of MSU in a
man or in straight catheter urine in women in a
complicated UTI.
 In a suprapubic bladder puncture specimen, any
count of bacteria is relevant

21. DRUG THERAPY OF UTIS
 Goals for treatment of UTI
1. Symptomatic relief by altering pH of urine
2. Eradication of infecting organisms
3. Prevention and treatment of recurrence
4. Identification and treatment of predisposing
factors

22. GENERAL PRINCIPLES
 In acute cases, an appropriate drug may be started
as soon as urine has been collected for
bacteriological examination.
 In chronic cases, mixed infection is more likely and
concomitant renal failure may modify drug therapy.
In such cases, there is no desperate hurry to start
drug treatment before case is thoroughly
investigated.

23. CONTD..
 Drug must be used in adequate doses and for
adequate periods.
 Growth of E.coli is optimum at pH 6 to 7 and is
inhibited at pH below 5.5 and above 7.5.
 pH of urine must also be maintained at a level that
would permit optimum antibacterial activity of drug
used.

24. CONTD..
 Fluid intake should be liberal as frequent emptying
of bladder helps
 To reduce bacterial count in urine and as growth of
E.Coli is reduced of urine is very dilute
 There is no satisfactory antibacterial drug to which
all the strains of E.coli are invariably sensitive.

25. CLASSIFICATION OF DRUGS
Bacteriostatic agents Bactericidal agents Urinary antiseptics
Sulfonamides Cotrimoxazole Nitrofurantoin
Tetracyclines Ampicillin Methenamine
mandelate
Nitrofurantoin Extended spectrum
penicillins
Nalidixic acid
Aminoglycosides
Fluroquinolones
Cephalosporins

26. SULFONAMIDES
 Bacteriostatic
 Most common drug used in E. coli infection
 Effective urine and tissue levels
 Development of bacterial resistance is a major
problem

27. COTRIMOXAZOLE
 Potent and cost effective bactericidal agent against
many common urinary tract pathogens.
 In acute uncomplicated UTI, it is used in dose of 2
tablets BID for 7-10 days.
 In small dose effective in eliminating chronic
bacteriuria.
 Trimethoprim concentrates in prostate.

28. AMPICILLIN
 Orally and parentally, Bactericidal.
 Good tissue levels and is excreted unchanged in
urine in high concentration.
 Dose of 0.5 g six hourly for 7-10 days.
 Useful for the treatment of UTI in pregnant women
 Hospital acquired infection are resistant

29. CARBENICILLIN
 Dose of 1gm four times a day.
 Useful in pseudomonas pyocyanea infection.

30. PIPERACILLIN
 Broad spectrum activity against gram negative
organism especially Pseudomonas Aeruginosa.
 For moderate infection 4-8 gms/ day I.V.
 For life threatening infection 12-16 gms/day
 Its use should be limited to severe UTIs with life
threatening septicemia

31. AMINOGLYCOSIDE ANTIBIOTICS
 Gentamicin and amikacin.
 Effective against E.coli, proteus and pseudomonas.
 Given parentally, Can cause ototoxicity and renal
toxicity.
 Single daily dose can reduce renal toxicity,
reserved for complicated UTIs

32. FLUROQUINOLONES
 Ideal agents for nosocomial pyelonephritis and
complicated UTIs.
 Norfloxacin, ciprofloxacin, ofloxacin, pefloxacin and
lomefloxacin.
 Highly effective orally.
 Effective against bacteria resistant to beta-lactam
and aminoglycoside antibiotics.

33. CEPHALOSPORINS
 Used in infection with E.coli and proteus resistant to
other antibiotics.
 DOC for klebsiella infection.
 3rd generation cephalosporins are effective against
multi-drug resistant enterobacteria and
pseudomonas.
 Septicemic UTI.

34. FOSFOMYCIN
 It is bactericidal against a range of gram-positive
and gram negative bacteria.
 A single 3g oral dose is used to treat uncomplicated
UTIs in women.
 Antibiotic fosfomycin may be prescribed as a single
dose treatment for women who are pregnant.

35. NITROFURANTOIN
 Rapidly absorbed from GIT.
 Urine concentration high but poor tissue
concentration.
 Unsuitable for renal parenchymal diseases.

36. CONTD..
 Used in chronic suppressive therapy in a dose of
50-100 mg/day for several weeks.
 Single indication of nitrofurantoin is treatment as
well as long term prophylaxis of lower UTIs mainly
E. coli.
 Safe in pregnancy.

37. NALIDIXIC ACID
 0.5 g Tablets.
 Dose is 4 gms /day in 4 divided dose for 7-10 days.
 Reserved for occasional cases with infection with
Proteus

38. METHANAMINE MANDELATE
 Salt of mandelic acid and methenamine.
 Rapidly absorbed from GIT, excreted in urine.
 At acidic pH less than 5.5, methenamine liberates
formaldehyde.
 Dose is 500mg q.i.d.

39. CONTD..
 Mandelic acid helps to lower urine pH.
 Not active against acute infection but used in
chronic suppressive therapy.
 Larger doses cause acute inflammation.

40. PHENAZOPYRIDINE
 It is dye exerts analgesic effects in UTIs
 Provides relieve from burning sensation, dysuria
and urgency due to cystitis.
 Devoid of antibacterial activity.
 Dose 200mg TDS orally.

41. CHOICE OF ANTIBACTERIAL THERAPY OF UTI
IS DETERMINED BY
 Site of infection in urinary tract.
 Whether a predisposing cause such as diabetes or
abnormality of urinary tract is absent
uncomplicated UTI or present complicated UTI.
 Whether infection is caused by drug sensitive or
drug resistant organism.

42. TREATMENT OF UTI (EMPIRICAL) ACUTE
UNCOMPLICATED CYSTITIS
3 day regimens 7 day regimen orally
•TMP-SMX 160/800 mg 12hourly Macrocrystalline nitrofurantoin
100 mg qid
•TMP 100 mg 12 hourly
•Norfloxacin 400 mg 12 hourly
•Ciprofloxacin 250 mg 12 hourly
•Oflaxacin 200 mg 12 hourly
•Levofloxacin 250 mg 12 hourly
•Gatifloxacin 200-400 mg /day
•Moxifloxacin 400 mg/day
•Lomefloxacin 400 mg/day

43. UNCOMPLICATED CYSTITIS IN WOMEN
 Women with diabetes, symptoms for >7days, recent
UTI, use of diaphragm, age >65 years, pregnancy
 7 day regimen orally
• Amoxicillin 250 mg 8 hourly
• Cefpodoxime proxetil 100 mg 12 hourly
• TMP-SMX 160/800 mg 12 hourly

44. ACUTE UNCOMPLICATED PYELONEPHRITIS
 In women most cases without associated clinical
evidence of calculi or urological disease
 Mild to moderate illness, no nausea or vomiting
 Oral quinolone for 7-14 day ( initial dose given I.V., if
desired), Single dose ceftriaxone 1g, Gentamicin 3-5
mg/kg, followed by oral TMP-SMX for 14 days

45. CONTD..
 In cases of severe illness or possible urosepsis:
hospitalisation required.
 Parenteral quinolone, gentamicin 1mg/kg 8 hourly,
ceftriaxone 1-2g/day until subside of fever.
 Oral quinolone, cephalosporin, or TMP-SMX for 14
days.

46. CLINICAL MANAGEMENT OF PYELONEPHRITIS

47. COMPLICATED UTIS
 In mild to moderate illness, oral quinolone for 10-14
days until culture results and antibiotic sensitivities
are known.
 In severe cases, parenteral therapy should be
started.
Parenteral Oral
Ampicillin 1g 6 hourly and
gentamicin 1mg/kg 8 hourly
Quinolones
Quinolone TMP-SMX
Ceftriaxone 1-2g/day
Ticarcillin/clavulanate 3.2 g 8
hourly
Imipenem/cilastatin 250-500 mg
8 hourly

48. POSTCOITAL CYSTITIS
 Some women get lower UTI following every sexual
intercourse.
 Initial treatment by suitable antibacterial drug.
 Followed by 0.5% cetrimide cream in periurethral
area before coitus and bladder emptying after every
sexual act.
 This may be followed by single dose Ampicillin or
TMP-SMX.

49. ASYMPTOMATIC BACTERIURIA
 Transient and resolves without treatment
 Removal of catheter followed by short course of
antibiotics
 If catheter can not be removed then use of systemic
antibiotic when symptoms appear

50. PROSTATITIS
Classification Clinical
Presentation
Prostat
e
EPS
(Expressed
prostatic
secretions)
Etiologic
Agent
Antibiotics
Acute bacterial
prostatitis
Acute onset of
fever, chills,
dysuria,
urgency
Tender,
tense,
boggy
PMNs,
bacteria
Escherichi
a coli,
other
uropathog
ens
Fluoroquinolo
ne, other
Chronic bacterial
prostatitis
Recurrent UTIs,
obstructive
symptoms,
perineal pain
Normal PMNs,
bacteria
E. coli,
other
uropathog
ens
Fluoroquinolo
ne, other

51. UTI IN CHILDREN
 Mostly first 3 months, UTI is more common in boys
3.7% than in girls (2%),
 After which incidence changes, being 3% in girls
and 1.1% in boys.
 Paediatric UTI is most common cause of fever of
unknown origin in boys less than 3 years.

52. CONTD..
 The clinical presentation of a UTI in infants and
young children can vary from fever to
gastrointestinal, lower or upper urinary tract
symptoms.
 Investigation should be undertaken after two
episodes of a UTI in girls and one in boys.

53. CRITERIA FOR DIAGNOSIS OF UTI
 Urine specimen from suprapubic aspiration
 Any number of CFU/mL
 Urine specimen from bladder puncture
catheterization
 > 1,000-50,000 CFU/mL
 Midstream clean catch
 > 104 CFU/mL with symptoms
 > 105 CFU/mL without Symptoms

54. TREATMENT OF UTI IN CHILDREN

55. VESICOURETERIC REFLUX (VUR)
 40-50% of infants and 30-40% chidren with UTI and
resolves with age.
 Its severity graded from I to V based on
appearance of urinary tract on micturating
cystourethrogram.
 Grade I-III are more likely to resolve.

56. UTI DUE TO CANDIDA
 Usually occurs with urinary catheters, typically after
antibiotic therapy
 At high risk are patients who are
immunocompromised because of tumor, AIDS,
chemotherapy.
 Asymptomatic candiduria rarely requires therapy.

57. CONTD..
 Candiduria should be treated in the following:
 Symptomatic patients
 Neutropenic patients
 Patients with renal allografts or
 Patients who are undergoing urologic manipulation

58. TREATMENT
 Catheters should be removed.
 Treatment with fluconazole 200 mg once/day for 7
to 14 days.
 I.V. amphotericin B.
 Bladder irrigation with amphotericin B.

59. ANTIMICROBIAL PROPHYLAXIS
 Indications
 Women of child bearing group.
 Catheterization or instrumentation inflicting trauma
 Uncorrectable congenital anamolies.
 Inoperable prostate enlargement or chronic obstruction.

60. CONTD..
 Drugs used for prophylaxis are
 All drugs are given once daily at bed time.
Cotrimoxazole 480mg
Nitrofurantoin 100mg
Norfloxacin 400mg
Cephalexin 250mg

61. CHLORAMPHENICOL
 Broad spectrum antibiotic – Bacteriostatic
 Inhibits protein synthesis – binds to 50S ribosome
subunit – causes inhibition of peptidyl transferase
 Undergoes enterohepatic circulation – inactivated
by hepatic glucuronidation
 Very few systemic use – due to
 Rapid development of resistance
 High toxicity

62.  Adverse effects –
 Dose dependent & reversible bone marrow suppression
 Idiosyncratic – irreversible myelosuppresion
 Neonates & premature infants – deficient in hepatic
glucuronyl transferase – leads to grey baby
syndrome

63. TETRACYCLINES
Binds to 30S ribosomal subunit – inhibits
binding of aminoacyl- t RNA to A site
Group I – tetracycline , chlortetracycline
, oxytetracycline
Group II – demeclocycline , lymecycline
Group III – doxcycline, minocycline

64.  Pharmacokinetics –
 Oral absorption – impaired by food and multivalent
cations
 Cross placenta - affect fetus
 Undergo enterohepatic circulation
 Excreted primarily in urine except doxycycline
 Doxcycline – excreted in feces

65.  Clinical uses –
 First choice of drugs –
1. Lymphogranuloma venereum (LGV)
2. Granuloma inguinale
3. Atypical pneumonia – chlamydia
4. Cholera
5. Brucellosis ( with rifampicin)
6. Plague prophylaxis
7. Relapsing fever ( Doxcycline)
8. Lymes disease ( Doxcycline)
9. Rickettsial infections ( Doxcycline)
10. Chlamydial infections ( Doxcycline)

66.  Toxicity –
1. Superinfection diarrhoea & pseudomembranous
colitis
2. Gastrointestinal side effects – most common
adverse effects
3. In Young children ( < 8 yrs ) – may cause dentition
abnormalities
4. Contraindicated – in pregnancy
 Fetal tooth enamel dysplasia
 Irregularities in fetal bone growth
5. Outdated tetracycline – fanconi’s syndrome

68. FINAFLOXACIN
 Phase III trials
 Marked increase at acidic pH
 Very high safety profile and wide spectrum.
 Longer t1/2 supportive of once daily dosing.

69. TETRACYCLINE
 Doxycycline, tetracycline, and minocycline.
 Used for infections that are caused
by Mycoplasma or Chlamydia.
 They cannot be taken by children or pregnant
women.

70. CONTD..
 Many infecting strains marked broader antimicrobial
resistance.
 Factors associated with an increase risk of
catheter-associated UTI include female sex,
prolonged catheterization, severe underlying
illness, disconnection of the catheter and drainage
tube, faulty catheter care and lack of systemic
antimicrobial therapy.

71. MANAGEMENT OF VUR
VUR grade Management
Grades I and II Antibiotic prophylaxis until 1 year
old. Restart antibiotic up to 5 yr of
age if breakthrough febrile UTI.
Grade III to V Antibiotic prophylaxis up to 5 year
of age. Consider surgery if
breakthrough febrile UTI.
Beyond 5 year: prophylaxis
continued if there is bowel bladder
dysfunction.

72. CONCLUSION
 Care must be taken in assessing individual patient.
 Drugs must be used in adequate doses and for
adequate period.
 Bactericidal drugs are to be preferred for treatment.
 All pregnant women should be screened in first
trimester and treated.
 For nosocomial UTIs
“prevention is better than cure”

73.  Sharma H.L.Quinolones and treatment of urinary
tract infections,Principal of pharmacology; 2nd
edition:708-715.
 Satoskar R.S.,Chemotherapy of urinary tract
infection, Pharmacology and
pharmacotherapeutics;22 edition:717-725
 Stamm W.E. Urinary tract infections,Harrison,
Principle of internal Medicine; 17th edition:1820-
1826

74. REFERENCES
 Petri W.A. Agents for urinary tract infection,
Goodman and Gilman, The pharmacological basis
of therapeutics;12 Edition:1463-1476
 Tripathi K.D..Urinary antiseptics,Essentials of
medical pharmacology; 7th edition: 760-764
 Katzung B.G. Treatment of Urinary Tract, Katzung
B. Basic and clinical pharmacology;11 edition:439-
450

75.  Indian society of Pediatric nephrology, Revised
statement on management of urinary tract infection,
vol 48, sept 17 2011, 709-717.