Urinary antiseptics

1. URINARY
ANTISEPTICS
DR. TITUS BEYUO (MD, MPHIL, MGCS, FWACS)
CONSULTANT OBGYN

2. OUTLINE
• Introduction
• Nitrofurantoin
• Nalidixic acid
• Methanamine
• Fluoroquinolones
• Sulfonamides
• Cotrimoxazole

3. ANTIMICROBIAL
AGENT/ANTIBIOTIC
• Antimicrobial agent: Chemical substance (synthetic or
natural) that inhibits or kills microorganisms
• Antibiotic: Chemical substance produced by
microorganisms that inhibits or kills other microorganisms

4. ANTISEPTIC VERSUS DISINFECTANT
Antiseptic An agent used to inhibit bacterial
growth in vitro and in vivo
Disinfectant An agent used to kill microorganisms
in an non-living environment

5. INTRODUCTION TO UTI
UTIs are prevalent in women of child-bearing age
and in the elderly population.
E. coli is the most common pathogen, causing
about 80% of uncomplicated upper and lower
UTIs. Staphylococcus saprophyticus is the second
most common bacterial pathogen causing UTIs.
In addition to cotrimoxazole and the quinolones,
UTIs may be treated with any one of a group of
agents called urinary tract antiseptics

6. INTRODUCTION TO UTI
Urinary antiseptics are oral drugs that are rapidly
excreted into the urine and act there to suppress
bacteriuria.
These drugs lack systemic antibacterial effects but
may be toxic.
Their usefulness is limited to the lower urinary
tract
Urinary antiseptics are often administered with
acidifying agents because low pH is an
independent inhibitor of bacterial growth in urine.

7. URINARY ANTISEPTICS
• These drugs include:
• NITROFURANTOIN
• METHANAMINE
• QUINOLONES

8. NITROFURANTOIN
This drug is active against many urinary tract
pathogens (but not Proteus or Pseudomonas), and
resistance emerges slowly. Mainly E. coli
Single daily doses of the drug can prevent
recurrent urinary tract infections, and acidification
of the urine enhances its activity.
The drug is active orally and is excreted in the
urine via filtration and secretion.
Should not be co-administered with Probenecid.---
-interferes with tubular secretion of probenecid

10. METHENAMINE
Methenamine mandelate and methenamine hippurate
combine urine acidification with the release of the
antibacterial compound formaldehyde at pH levels
lower than 5.5.
 These drugs are not usually active against Proteus
because these organisms alkalinize the urine.
Insoluble complexes form between formaldehyde and
sulfonamides, and the drugs should not be used
together.

11. QUINOLONES
History
• Obtained from chloroquine
Chemistry
• 4-quinolone ring
• Nalidixic acid first to be used clinically
Problems
• Poor tissue penetration
• Narrow antibacterial spectrum
• Relegated to treatment of UTI

12. NALIDIXIC ACID
This quinolone drug acts against many gram-negative
organisms (but not Proteus or Pseudomonas) by
mechanisms that may involve acidification or
inhibition of DNA gyrase.
The drug is active orally and is excreted in the urine
partly unchanged and partly as the inactive
glucuronide.
Toxic effects : include gastrointestinal irritation,
glycosuria, skin rashes, phototoxicity, visual
disturbances, and CNS stimulation.
Nitrofurantoin may antagonize the action of nalidixic
acid.

14. FLUOROQUINOLONES
History
• Substitution on ring at position 6 with F → Fluoroquinolones → anti G-ve
activity
• Substitution on position 7 →↑tissue penetration
• Substitution on position 8 → antimicrobial activity
• Fluoroquinolone (metabolism)  active metabolites
• Substitutions & metabolism → Generations of fluoroquinolones

15. FLUOROQUINOLONES
Ist
Generation
Drugs
• Nalidixic acid
Antimicrobial Activity
• G-ve, except Pseudomonas
Special indication
• Uncomplicated UTI

16. FLUOROQUINOLONES
2nd Generation
Drugs
• **Norfloxacin**, Lomefloxacin, Ofloxacin, Ciprofloxacin
Antimicrobial Activity
• G-ve + Pseudomonas
• Some G+ve except Strep. pneumoniae
• Chlamydia
• Mycoplasma
• Legionella B. anthracis

17. FLUOROQUINOLONES
2nd Generation
Special Indications
• Respiratory Infections
• UTI
• STD
• Pyelonephritis
• Prostatitis
• Skin, soft tissue infections
• Osteomyelitis (deep penetrating activity)
• anthrax

18. FLUOROQUINOLONES
3rd
Generation
Drugs
• Levofloxacin, Sparfloxacin, Gatifloxacin, Moxifloxacin, Grepafloxacin
(Respiratory Fl-Qs)
Antimicrobial Activity
• Same as 2nd Generation
• +↑G-ve
• + Pen-sensitive & Pen-resistant esp. Strep. pneumoniae

19. FLUOROQUINOLONES
(3rd
Generation contd)
Special Indications
• exacerbated acute chronic bronchitis
• Community acquired pneumonia

20. FLUOROQUINOLONES
4th
Generation
Drugs
• Trovafloxacin
Antimicrobial Activity
• Same as 3rd Generation + ↑ Anaerobic coverage
Special Indications
• Same as 3rd Generation not UTI’s & Pyelonephritis
• Intra-abdominal infections, PID, Nosocomial pneumonia

21. FLUOROQUINOLONES
MoA
• Quinolones & Fl-quinolones inhibit topoisomerase II (DNA-gyrase) &
topoisomerase IV
• Enzymes responsible for zipping & unzipping of the DNA strands
• Zipping & unzipping → bacterial cell repairs & replication
• Bactericidal; Effectiveness is concentation dependent

22. FLUOROQUINOLONES
Resistance
• Alteration in topoisomerase enzymes
• ↓ permeability
• Efflux mechanism

23. FLUOROQUINOLONES
PK
• Mostly well absorbed given PO
• Empty stomach appear to aid absorption
• Form complexes with Ca++, Fe++, Mg++, Al++ etc.  absorption
• Avoid concomitant administration with antacids
Solution
• IV–versions available

24. FLUOROQUINOLONES
PK
• Protein binding = 10-80% (variable)
• Elimination = Hepatic/Renal/both
• T½ = 3½-30 h (variable)
• Enterohepatic recycling (some Fl-quinolones)

25. FLUOROQUINOLONES
Therapeutic Use
• Broad spectrum
1.Diarrhea
• Active against G-ve enteric bacteria, esp.
• Salmonellosis (Enteric fever)
• Shigella
• Campylobacter

26. FLUOROQUINOLONES
Therapeutic Uses
2. UTI
• Though not strictly urinary antiseptic (has systemic effect)
• Very effective against UTI agents
• Gonococcal infection
• PID

27. FLUOROQUINOLONES
3. Soft & Deep Tissues
• Skin, joints & bones (osteomyelitis) (due to drug’s good penetrating activity)
4. Respiratory Infections
• Haemophilus spp.
• Strept. pneumonia; Strept. fecalis (G+ve)
• Pneumococcal pneumonia (esp. 3rd & 4th gen)
• Anthrax

28. FLUOROQUINOLONES
Side effects
• Arthropathy → not recommended for treatment in pregnant women, nursing
mothers & growing children
• Achilles tendonitis → rupture of tendon (esp. geriatric patients)
• Crystalluria (except levo-, gati-, moxi-, & trovafloxacin) → (Advise: fluid
intake)
• GIT disturbances
• Photosensitivity

29. FLUOROQUINOLONES
Rare but dangerous side effects
• Cardiac → QT prolongation (Torsades de pointes (twisting of the pointes 
ventricular arrhythmia) due to halogen substitution at position 8?) → esp
Grepafloxacin (withdrawn)
• CNS → insomnia, dizziness, anxiety, seizure (when taken + theophilline or
NSAIDS)
• Hepatotoxicity → esp trovafloxacin → limited to very serious conditions in
hospitals
• Hematuria esp. G-6-PD deficient patients?

30. FLUOROQUINOLONES
Drug Interactions
• Fl-Q +Antacids, Milk products etc containing Al++, Mg++, Fe++, Zn++, Ca++
→↓absorption
• Fl-Q + NSAIDS → CNS disturbances (due to displacement of GABA from its
receptors?)
• Fl-Q + Theophylline (Methylxanthines) → (Cytocr P450 inhibition?) 
↑[Theophylline]  Theophylline toxicity in asthmatics (Toxicity =
nausea+vomoting, GIT-dist, Seizures, etc)

31. FLUOROQUINOLONES
Drug Interactions
• Fl-Q + Warfarin →↑ Prothrombin time
• Fl-Q + Alkalizing agents → Crystalluria (advise ↑fluid
intake)

32. SULFONAMIDES
History
• Prontosil prevented Streptococcal infections in mice (Gerhard Domagk, 1935)
• Prontosil used to treat puerperal sepsis (fever at child-birth) (Gerhard Domagk, 1936)
• Prontosil → sulfanilamide → all sulfonamides
• First synthetic antimicrobial agent

33. SULFONAMIDES
Reason for Microbial Susceptibility
• Folic acid used by mammals & prokaryotes  DNA & RNA
Source of folic acid
• Mammals  diet
 transport mechanism

34. SULFONAMIDES
• Prokaryotes  biochemical synthesis
Sulfonamide sensitivity
• Prokaryote Dihydropteroate Synthase >> Mammalian Dihydropteroate Synthase

35. SULFONAMIDES
MoA
• Pteridine + PABA + Glutamic acid = Folic acid
• Folic acid → purine & pyrimidine synthesis (1-Carbon donors) → DNA synthesis
• Sulfonamides = Structural analogs of PABA
• Interfere with folic acid synthesis → ↓ DNA synthesis

36. SULFONAMIDES
Dihydropteroate Synthase
PABA + Pteridine  Dihydropteroic acid (Dihydrofolic acid) 
Sulfonamide
Dihydrofolate Reductase
 Tetrahydrofolic acid  Purines + Pyrimidines  DNA
Trimethoprim

37. SULFONAMIDES
Resistance
• 1. ↑ Synthesis of PABA
- PABA from pus competes with sulfonamides
- *Procaine → PABA esters ’’ ’’ ’’*
• 2. Altered bacterial dihydropteroate synthase  sulfonamide affinity
• 3. Bacteria bypasses 1-Carbon synthesis of bases pathway
(R-plasmids responsible)
• *X-resistance to sulfonamides & other drugs evident*

38. SULFONAMIDES
PK
• Absorption = Readily absorbed; usually given PO or topically
• Distribution = Vd; distributes in bodily water, enter CNS, synovial, milk & ocular
fluids, fetal circulation  fetus
• ↑ Protein binding → displaces bilirubin → bilirubin in basal ganglia & Subthalamic
Nucl  kernicterus (neonates)
Caution: Not to be given to near-term pregnant women or neonates (2 months before
term)

39. SULFONAMIDES
PK
• Metabolism = hepatic (very little)
- acetylation of amino-group;
- oxidation of aromatic ring/side chain
• Elimination = renal (mostly unchanged); useful in UTI

40. SULFONAMIDES
Short Acting
• Sulfisoxazole
• Sulfamethozaxole
• Sulfadiazine
Characteristics
• T½ = short (6-9 h)
• Rapidly absorbed & excreted
Long Acting
• Sulfadimethoxine
• Sulfadoxine
• Sulfadiazine (topical)
• Sulfacetamide ’’
Characteristics
T½ = long (10-17 h; 7-9
days)
• Poorly excreted useful in
protozoal infection esp. in
AIDS patients

41. SULFONAMIDES
Reasons for differences in T½
•  Protein binding   T½
•  Tubular reabsorption   T½

42. SULFONAMIDES
Antimicrobial spectrum
• Broad
• Bacteriostatic
• G+ve & G-ve bacteria
• Chlamydia
• Toxoplasma gondii
• Chloroquine-resistant Plasmodium falciparum
• S + trimethoprim  effective Pneumocystis carinii
(AIDS patients)

43. SULFONAMIDES
Ther. Use
• Bacteriostatic
• Limited by resistance problems
• Sulfonamides + trimethoprim (cotrimoxazole) = ↑ usefulness
• UTI, esp. caused by E.coli
• GI-infections by E.coli, Yersinia, Salmonella sp. (Caution: resistance in G-ve
bacteria)

44. SULFONAMIDES
Ther. Use
• Protozoal & fungal infections (respond poorly to antibiotics)
- Chlamydia, nocardia, toxoplasma
- Chloroqine-resistant P. falciparum
- Pneumocystis carinii (fungus?) in AIDS patients

45. SULFONAMIDES
Toxicity
• Renal - older ones crystallize in urine (advise ↑ fluid intake)
• Blood dyscrasias – hemolytic anemia (G-6-PD deficient patients), agranulocytosis,
aplastic anemia, thrombocytopenia
• Hypersensitivity (Dermal) – rash, pruritus, erythema, exfoliative dermatitis (Stevens-
Johnson’s syndrome)
• S-J’s syndrome blisters of skin, mouth, eyes & genitalia; & kidney failure

46. SULFONAMIDES
Toxicity
• Hypersensitivity: All sulfonamides are X-allergenic including S-containing drugs;
- carbonic anhydrase inhibitors
- thiazides
- furosemide
- sulfonylureas

47. TRIMETHOPRIM
History
• Introduced since 1969 in synergism + sulfonamides →↓
resistance to sulfonamide
• Cotrimoxazole = 1 trimethoprim:5 sulfamethoxazole

48. TRIMETHOPRIM
MoA
Dihydrofolate reductase
• H2folic acid → H4folic acid → Purine + Pyrimidines → DNA synthesis
Trimethoprim

49. TRIMETHOPRIM
Resistance
• 1.  Cellular permeability
• 2. Altered target enzyme
• 3.  Enzyme production
• 4. Selection of microbes that lack step for folic acid synthesis (plasmid
mediated)  natural selection (recent findings)

50. TRIMETHOPRIM
PK
• Absorption = usually given PO; well absorbed: Tmax = 2 h
• Distribution = Vd; all tissues, including CSF, eye, prostate, vaginal fluid etc.
• Excretion = hepatic (1/3) + (2/3) Renal  GFR (unchanged)
• Rate of elimination in neonates = 2x that of adults

51. TRIMETHOPRIM
Ther. Use
• Trimethoprim  little antibacterial activity
• Trimethoprim + Sulfamethoxazole (1:5)  (cotrimoxazole)  antibacterial
activity
Reason for combination
• Antibacterial activity
• Identical T½
•  Resistance to both drugs
•  Susceptibility = Most organisms except Pseudomonas

52. COTRIMOXAZOLE
Ther. Use
• Respiratory infections
- Bronchitis (Streptococcus pneumonia; Haemophilus influenzae)
- Pneumocystis carinii (fungus?)
• Gonorrhea
• Nocardial infections
• GI infections due to G-ve bacteria (salmonella)

53. COTRIMOXAZOLE
Toxicity
• GI – upset
• Bone marrow depression  megaloblastic anaemia
Mitigation:
co-administer folic acid
• Renal toxicity   Creatinine (renal insufficiency)
• Skin rash

54. THANK YOU FOR THE AUDIENCE
• Any questions?????