Agents For UTI

Question 1

Sulfonamides

Answer 1

􏰀 1st effective chemotherapeutic agents for the prevention and cure of bacterial infections

􏰀 Wide range of activity against both gm – and gm + bacteria

􏰀 Bacteriostatic

􏰀 Spectrum: S. pyogenes, S. pneumoniae, H. influenzae, H. ducreyi, Nocardia, Actinomyces, C. trachomatis

􏰀 N. meningitidis, Shigella, E. coli-resistant

􏰀 MOA: competitive antagonists of para-aminobenzoic acid (PABA) —> Prevent normal bacterial utilization of PABA for synthesis of folic acid
􏰀 Also, competitive inhibitors of dihydropteroate synthase —> incorporation of PABA into dihydropteroic acid
􏰀 Synergistic w/ Trimethoprim —> potent and selective competitive inhibitor of dihydrofolate reductase

􏰀 ABSORPTION, FATE AND EXCRETION
􏰀 70-100% of dose absorbed
- Absorbed rapidly from GIT
- Found w/in 30 min in urine
- Peak plasma levels-2-6 hrs
- Small intestine-major site of absorption
- Readily pass through placenta

􏰀 Classification:
- Agents that are rapidly absorbed and excreted
Sulfisoxazole
Sulfadiazine
- Agents that are absorbed very poorly p.o. —> active in bowel lumen
Sulfasalazine
- Agents used mainly topically
Sulfacetamide
Mafenide
Silver sulfadiazine
- Long-acting : absorbed rapidly but excreted slowly
Sulfadoxine

Question 2

RAPIDLY ABSORBED AND ELIMINATED

Answer 2

SULFISOXAZOLE
􏰄 Excellent antibacterial activity
􏰄 Sulfisoxazole acetyl – tasteless; oral use in children
- Marketed in combination w/ Erythromycin ethylsuccinate for otitis media in children
- Urine becomes orange-red-due to phenazopyridine
- May produce hematuria or crystalluria
Patients should ingest an adequate quantity of water
Caution in patients w/ impaired renal function
- May produce hypersensitivity reactions

SULFAMETHOXAZOLE
􏰄 Systemic and UTI
􏰄 Marketed in fixed-dose combinations w/ Trimethoprim
􏰄 Produces crystalluria-high % of insoluble form of drug in urine

SULFADIAZINE
􏰄 Ensure adequate fluid intake —> UO at least 1200 ml in adults

Question 3

POORLY ABSORBED SULFONAMIDES

Answer 3

SULFASALAZINE
􏰄 Very poorly absorbed from GIT
􏰄 Tx of mild or moderate ulcerative colitis
􏰄 1st drug for mild cases of regional enteritis and
granulomatous colitis

􏰄 Broken down to:
— Sulfapyridine – resp. for most of toxicity
— 5-aminosalicylate-effective agent

􏰄 Toxic reactions: Heinz-body anemia, acute hemolysis in
pts w/ G6PD def, agranulocytosis
— Also, N, fever, rashes, arthralgias

Question 4

SULFONAMIDES FOR TOPICAL USE

Answer 4

SULFACETAMIDE
􏰀 Management of ophthalmic infections
􏰀 Very high conc not irritating to eye, effective against susceptible org

SILVER SULFADIAZINE
􏰀 Used topically to reduce microbial colonization and incidence of infections of wounds from burns
􏰀 Not used to treat an established deep infection
􏰀 Adverse rxns-burning, rash, itching-infrequent

MAFENIDE
􏰀 Prevention of colonization of burns by a large variety of gm – and gm + bacteria
􏰀 Applied 1-2x daily 1-2 mm thick over burned skin
􏰀 Cleansing of wound and removal of debris done before each application
􏰀 Tx continued until skin grafting done
􏰀 Adverse effects:
— Intense pain at site of application
— Allergic reactions
— Loss of fluid of evaporation from burn surface

Question 5

LONG-ACTING SULFONAMIDES

Answer 5

Sulfadoxine

􏰀 Long t 1⁄2 -7-9 days
􏰀 Combined w/ Pyrimethamine
􏰀 For prophylaxis and treatment of malaria caused by Mefloquine-resistant strains of Plasmodium falciparum
􏰀 Should only be used for prophylaxis in high risk
resistant malaria areas
— Due to severe and sometimes fatal reactions

Question 6

SULFONAMIDE THERAPY

Answer 6

URINARY TRACT INFECTIONS
􏰀 No longer 1st choice-due to resistance
􏰀 TMP-SMX, quinolone, Fosfomycin, Ampicillin=preferred agents

􏰀 Sulfisoxazole-may be used in areas where resistance is not high
— 2-4 g initially ffd by 1-2 g orally q 6H for 5-10 days

􏰀 Pts w/ acute pyelonephritis
— At high risk for bacteremia and shock
— Not treated w/ Sulfonamides

􏰀 Nocardiosis
— Sulfisoxazole or Sulfadiazine 6-8 g daily

􏰀 Toxoplasmosis
— Pyrimethamine and Sulfadiazine-DOC

􏰀 Use of Sulfonamides for prophylaxis
— As efficient as oral PCN in preventing Strep infections and recurrences of RF

􏰀 Untoward Reactions
— Disturbances of Urinary Tract
Crystalluria
w/ older, less soluble sulfonamides
Lesser w/ Sulfisoxazole
Fluid intake sufficient to ensure daily volume
of urine at least 1200 ml (adults)
— Disorders of the Hematopoietic system
Acute hemolytic anemia
Sensitization phenomenon
Agranulocytosis
Aplastic anemia

􏰅 Hypersensitivity reactions
— Occur most often during 1st week of therapy
— Morbilliform, scarlatinal, urticarial, erysipeloid,
pemphigoid, purpuric, petechial rashes
— Erythema nodosum
— Erythema multiforme
— Fever, malaise, pruritus

􏰀 Miscellaneous reactions
— Anorexia, N & V
— Newborn infants-kernicterus
Displacement of bilirubin from plasma albumin
— Not given to pregnant women near term

􏰄 Drug Interactions
— Oral anticoagulant, sulfonylureas, hydantoin anticonvulsants
— Potentiate effects of these drugs

Question 7

TRIMETHOPRIM-SULFAMETHOXAZOLE

Answer 7

􏰀 Co-trimoxazole
􏰀 synergistic

􏰀 Antibacterial spectrum
— Resistant
􏰄 P. aeruginosa
􏰄 B. fragilis
􏰄 Enterococci
— Sensitive
􏰄 C. diphtheriae
􏰄 N. meningitidis
􏰄 S. aureus, s. epidermidis
􏰄 S. pyogenes, the viridans group
􏰄 E. coli
􏰄 P. mirabilis, p. morganii, p. rettgeri
􏰄 Enterobacter sp.
􏰄 Salmonella, Shigella, Klebsiella

􏰄 MOA: actions on 2 steps of the enzyme pathway for the synthesis of tetrahydrofolic acid

􏰄 Absorption, Distribution, Excretion
— 20:1 conc(SMZ-TMP)
— Readily enters CSF and sputum
— TMP absorbed > rapidly than SMZ
— T1⁄2-10and11hours

􏰄 Therapeutic Uses
— UTI
Acute uncomplicated UTI
Chronic and recurrent UTI
200mg SMZ plus 40 mg TMP per day/4x dose 1-2x per week
Presence of tx conc of TMP in vaginal sec.

􏰇 Therapeutic Uses
— UTI
Acute uncomplicated UTI
Chronic and recurrent UTI
200mg SMZ plus 40 mg TMP per day/4x dose 1-2x per week
Presence of tx conc of TMP in vaginal sec.
TMP: also found in tx conc. In prostatic secretions

— Bacterial Respiratory Tract infections
Acute exacerbations of Chronic Bronchitis
􏰈 800-1200 mg SMZ plus 160-240 mg TMP
Not used to treat Strep pharyngitis
􏰈 Does not eradicate organism
Acute OM in children
Acute Maxillary Sinusitis in adults

— GIT Infections
􏰉 Alternative to Fluoroquinolone for Shigellosis
􏰉 2nd line for typhoid fever
􏰉 Mgt of carriers of S. typhi and other sp.
800/160 mg BID x 2 months

— Infection by Pneumocystis jiroveci
􏰉 High dose tx (100 mg/kg/15 mg/kg) 3-4x per
day
􏰉 Patients w/ AIDS

— Untoward Effects
􏰉 Folate deficiency
Megaloblastosis, leukopenia or thrombocytopenia
􏰉 Skin effects
Stevens-Johnson syndrome, toxic
epidermal necrolysis􏰁rare
􏰉 GI :N and V; diarrhea-rare
􏰉 Glossitis, stomatitis — common
􏰉 CNS reactions:
Headache
Depression
Hallucinations
􏰉 Hematologic
Anemias
Coagulation disorders
Granulocytopenia
Agranulocytosis
Henoch-Schonlein purpura

Question 8

QUINOLONES

Answer 8

Nalidixicacid
Cinoxacin
Fluoroquinolones
∙ Norfloxacin
∙ Ciprofloxacin
∙ Ofloxacin
∙ Sparfloxacin
∙ Fleroxacin
∙ Pefloxacin
∙ Levofloxacin
∙ Garenoxacin
∙ Gemifloxacin

MOA: inhibits topoisomerase IV (gram + bact) 􏰆 Inhibits DNA gyrase (gram – bact)

Fluoroquinolones-bactericidal
􏰆 E. coli
􏰆 Salmonella
􏰆 Shigella
-Neisseria -Enterobacter -Campylobacter

􏰊 P.aeruginosa
— Ciprofloxacin>Norfloxacin

􏰊 NotactiveagainstMRSA

􏰊 Streptococci
— Levofloxacin
— Gatifloxacin
— Moxifloxacin

Inhibitstheff:
􏰆 Chlamydia
􏰆 Mycoplasma
􏰆 Legionella
􏰆 Brucella
􏰆 Mycobacterium (including M. Tb)

Anaerobicbacteria
􏰆 Garenoxacin, Gemifloxacin

Absorption,FateandExcretion
􏰆 Well absorbed orally
􏰆 Norfloxacin-low serum levels
- Use limited to tx of UTI
􏰆 Food-delay time to peak serum conc.
􏰆 Dose:
- Ofloxacin-200-400 mg q 12h
- Norfloxacin, Pefloxacin-400 mg q 12h
- Ciprofloxacin-250-500 mg q 12h

Highvolumeofdistribution
􏰆 Esp. in urine, kidney, lung, prostate tissue,
stool, bile, macrophages, neutrophils

Clearedpred.bykidneys
􏰆 Except Pefloxacin, Moxifloxacin-liver 􏰊

Therapeuticuses:
􏰆 UTI
- Nalidixic acid-susceptible organisms
- Norfloxacin – only for UTI
- Fluoroquinolones->potent than TMP-
SMX
􏰆 Prostatitis
- Norfloxacin
- Ciprofloxacin
- Ofloxacin
􏰆 STD
- contraIx in pregnancy
- Active against N. gonorrhea, C. trachomatis, H. ducreyi
- Lack activity against T. pallidum
- Chlamydial urethritis/cervicitis
— 7 day Ofloxacin or Sparfloxacin
— Alt. to 7 days of Doxycycline or
single dose of Azithromycin
— However, in newer studies have
high resistance
- PID: 14 days Ofloxacin + Clindamycin
or Metronidazole
􏰆 GIT and Abdominal infections
- Shigellosis
􏰅 Norfloxacin, Ciprofloxacin,
Ofloxacin x 5d
- S. typhi
􏰅 Ciprofloxacin, Ofloxacin

􏰆 Respiratory Tract Infections
- Excellent activity against s. pneumonia
- Ciprofloxacin, Levofloxacin
􏰅 DOC for L. pneumonia

􏰆 Osteomyelitis
- 4-6 weeks or more
- 500-750 mg BID

􏰈 Other Infections
Ciprofloxacin-prophylaxis of Anthrax Treatment of tularemia
Part of multi-drug regimen for MDRTB

􏰈 Adverse effects
GI-mild nausea, vomiting, abdominal discomfort Diarrhea
CNS-mild headache, dizziness
Rarely-hallucinations, delirium, seizures
Rashes
Photosensitivity
Achilles tendon rupture, tendinitis

Contraindicated in children due to arthropathy

Question 9

URINARY ANTISEPTICS AND ANALGESICS

Answer 9

METHENAMINE
􏰋 Generates formaldehyde-responsible for antibacterial action
􏰋 Absorbed orally, 10-30% decomposes in gastric juice —> enteric coat
􏰋 contraIx in hepatic insufficiency-due to ammonia production
􏰋 Given together with urine acidifiers (Mandelic acid, hippuric acid)—increase activity
􏰋 GI distress-w/ dose>500 mg QID
􏰋 Dose of 4-8 g/day x >3-4 weeks
— Painful and frequent micturition
— Albuminuria
— Hematuria
— Rashes
􏰋 Mutually antagonistic w/ Sulfonamides
􏰋 Therapeutic uses
— Not 1st line drug for UTI
— For chronic suppressive therapy
— Most useful for E. coli

NITROFURANTOIN
􏰋 Forms intermediates responsible for damage to
bacterial DNA
􏰋 Approved only for Tx of UTI caused by susc. Org 􏰋 2nd line agenta
􏰋 Absorbed rapidly and completely from GIT
􏰋 Urine should not be alkalinized
􏰋 Turns urine brown
􏰋 Most common S/E:
— N,V, diarrhea
􏰋 Hypersensitivity reactions
— Chills
— Fever
— Leukopenia
— Granulocytopenia
— Hemolytic anemia
— Cholestatic jaundice
— Hepatocellular damage
􏰋 Neurological disorders-headache, vertigo, drowsiness, muscle aches, nystagmus
􏰋 Dose: 50-100 mg 4x a day with meals and at bedtime
— Should not exceed 14 days
— Repeat courses separated by rest periods
— contraIx in pregnant women, children<1
month, crea clearance<40 ml/min
􏰋 Tx of susceptible org
— E. coli
— Enterococci
􏰋 Not recommended for Tx of pyelonephritis or prostatitis
􏰋 For prophylaxis of of recurrent UTI

PHENAZOPYRIDINE
􏰋 Not an antiseptic
􏰋 Urinary analgesic
􏰋 Alleviates dysuria, frequency, burning and urgency
􏰋 Dose: 200 mg TID
􏰋 Azo dye – colors urine orange or red