SINGLE DOSE treatment of URINARY TRACT INFECTION in women, Dr Sharda jain , Dr. jyoti Agarwal , Dr....

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SINGLE DOSE treatment of URINARY TRACT INFECTION in women

Dr. Sharda JainDr. Jyoti Agarwal

Dr. Jyoti Bhaskar

Our Teamdedicated for giving knowledge &skill to doctors

E coli is the biggest culprit

• UTI is the 2nd most common infectious presentation in community practices

• World wide, about 150 million people are diagnosed with UTI each year

Ann Clin Micr Anti 2007; 6: 4-12

Urinary Tract Infection (UTI)

Risk Factors Associated with UTIs

Uncompliced Complicated•Sexual intercourse•Spermicide creams•Diaphragm•Previous UTI

• Pregnancy• Catheterization• Diabetes• Infection stones• Male• Elderly

Medicine.2007; 35: 423-427

Causative Organisms

Acute Uncomplicated cystitis

E.coli: 70 - 95%Staphylococcus saprophyticus: 10 -15%Klebsiella spp. Proteus mirabilis

Arch Intern Med.2007; 167: 2207-12

Symptoms of Uncomplicated cystitis

If both dysuria and frequency are present in the absence of vaginal discharge, the chance of UTI is ~90%.

Dysuria Frequency Urgency Hematuria Suprapubic pain

Campbells Urology 2007; 9th Ed

Treatment for Uncomplicated Cystitis

Short term antibiotics recommended by EAU guidelines as drug of first choice

Drug Dose Duration

Fosfomycin trometamol

3 g SD 1 day

Nitrofurantoin 50 mg q6h 7 days

Nitrofurantoinmacrocrystals

100 mg bid 5-7days

Pivmecillinam 400 mg bid 3 days

Pivmecillinam 200 mg tid 5 days

EAU Guidelines 2014

Drug Dose Duration

3 g SD 1 day

100 mg bid 5-7days

EAU Guidelines 2014

Drug Dose Duration

3 g SD 1 day

100 mg bid 5-7days

EAU Guidelines 2014

Choice of antibiotic should take into account not only the spectrum of activity but also resistance

Currently used antibiotics in the management of acute uncomplicated cystitis are:

• Fluoroquinolones• Cephalosporins• Amoxicillin-clavulanate

However, there are certain gaps in the current antimicrobial therapy of

acute uncomplicated cystitis……

1. Not recommended by guidelines as a “drug of first choice”1

• Fluoroquinolones: Resistance is increasing2

Have propensity for collateral damage3

Should be reserved for important uses other than acute cystitis.3

• Amoxicillin-clavulanate and Cephalosporins: Have inferior efficacy and more adverse effects3

Resistance is increasing4

2. Longer duration of therapy1,3

Duration of therapy is for 3-5 days

1. EAU Guidelines on Urological Infections 20132. BJU Int 2008; 102: 1634-16373. IDSA Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in women 20104. BMC Infect Dis 2012; 12: 222-229

To address these gaps in the management of acute uncomplicated cystitis with first-line single-dose therapy….

Introducing…

New antibiotic option

on horizon for first-

line treatment of

acute uncomplicated

cystitis

Fosfomycin Trometamol Powder

Composition

Each sachet contains:

Fosfomycin Trometamol BP equivalent to Fosfomycin …...3.0 gmExcipients...............................................................................q.s.

Fosfomycin

• Fosfomycin was discovered in 1969 in Spain.

• It is a phosphonic acid derivative.

• It’s a broad-spectrum bactericidal antibiotic with activity against both Gram-positive and Gram-negative bacteria

Int J Infect Dis 2011; 15(11): e732-e739

Pharmacology

Pharmacodynamics

Mechanism of Action

• Fosfomycin inhibitis the cell wall synthesis of bacteria.1

Fosfomycin interferes with the first committed step in peptidoglycan biosynthesis.

It inactivates enzyme enolpyruvyl transferase (MurA) thus it inhibits the formation of N-acetylmuramic acid from N-acetylglucosamine and phosphoenolpyruvate.

• It also reduces adherence of bacteria to uroepithelial cells.2

1. Drugs 2013; 73: 1951–19662. Drugs @ FDA as assessed on 4/9/14

Video on Cell Wall Synthesis

Mechanism of Action of Fosfomycin

N-acetylmuramic acid

Spectrum of Activity of Fosfomycin

• Gram-positive Microorganisms Enterococcus faecalis Staphylococcus saprophyticus

• Gram-negative Microorganisms Escherichia coli Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa

Drugs 2013; 73: 1951–1966

PharmacologyPharmacokinetics

•Absorption:Fosfomycin trometamol is rapidly absorbed following oral administration and converted to the free acid, fosfomycin.After a single 3 gm dose of fosfomycin trometamol, the Cmax achieved was 26.1 μg/mL within 2 hours.

•Distribution: Fosfomycin is distributed to the kidneys, bladder wall, prostate, and seminal vesicles.

•Excretion: Fosfomycin is excreted unchanged in both urine and feces.Around 38% of a 3 gm dose of fosfomycin trometamol is recovered in urine and 18% is recovered in feces. Urinary concentrations equal to or greater than 100 µg/mL were maintained for 26 hours.The mean half-life for elimination (t1/2) is 5.7 hours.

Drugs @ FDA as assessed on 4/9/14

Indication

For the treatment of uncomplicated urinary tract infections (acute cystitis) in women due to susceptible strains of Escherichia coli and

Enterococcus faecalis

Unique Features of Fosfomycin

• High susceptibility against E.coli1

• Optimum urinary concentration allows once daily dosing2

• Lower resistance rates even after long-term usage1

• Established efficacy and safety with single-dose therapy3

• Better patient compliance4

1. Diagn Microbiol Infect Dis 2010; 66: 87-932. Infectious Disease in Clinical Practice 2001; 10: 255-2603. Chemotherapy 2005; 51: 162-1664. Drugs 2013; 73: 1951–1966

High Susceptibility of Fosfomycin Against E.coli

Study Design

•A prospective multicenter study was conducted between 2006 and 2008 which included 352 adult women (aged ≥18 years) with outpatient diagnosis of uncomplicated cystitis. A midstream urine sample from all patients was obtained for culture.

•The antimicrobial susceptibility of E. coli isolates from 271 patients to the drugs that are commonly used for outpatient treatment of uncomplicated cystitis was assessed.

•Antimicrobial susceptibility testing was performed by the disk diffusion method in accordance with the Clinical and Laboratory Standards Institute (2007) recommendation.

Diagn Microbiol Infect Dis 2010; 66: 87-93

Result

Fosfomycin showed higher susceptibility against E.coli as compared to other antimicrobial agents.

Fosfomycin should be used as initial therapy for empiric treatment of uncomplicated cystitis in

women.

Conclusion

Optimal Urinary Concentration

•After a single 3 g dose of fosfomycin, high urinary levels (>128 mg/L) are maintained for at least 36 to 48 hours and sufficient to inhibit most urinary pathogens.1

1. Infectious Diseases in Clinical Practice 2001; 10: 255–2602. Clin Microbiol Infect 2012; 18(1): 4-7

Longer half-life and high urinary concentration makes it suitable for single-dose therapy of uncomplicated UTIs.2

Lower Resistance Rates Even After Long-term Usage

Study Design

•A survey was conducted in Genoa between September–November 2000 to monitor the trends of resistance to fosfomycin trometamol and other antibiotics such as norfloxacin, nitrofurantoin and cotrimoxazole in the primary pathogens of uncomplicated UTI. •This survey included all Gram-negative uropathogens isolated from outpatients.

•The trend in the prevalence of the drug resistance for urinary E.coli was compared over a 10-year period.

Fosfomycin was the only drug that did not suffer from an increase in the incidence of resistance over a 10-year period

as compared to other antibiotics.

45 fold

2.2 fold

0 fold

Int J Antimicrob Agents 2003; 22: S79-S83

Result

Fosfomycin trometamol due to its low resistance rate remains a drug of choice for the eradication of

uncomplicated UTI.

Int J Antimicrob Agents 2003; 22: S79-S83

Conclusion

Better Compliance with Single-dose Therapy

Fosfomycin offers convenient dosing schedule with single-dose therapy and has following advantages1,2

•low risk of resistance•low risk of adverse events•better compliance

1. Infectious Diseases in Clinical Practice 2001; 10: 255–2602. Drugs 2013; 73: 1951-1966

Dosage and Administration

•The recommended dosage for women, 18 years of age and older is one sachet of FOSIROL.

•It may be taken with or without food.

•FOSIROL should not be taken in the dry form. Always mix FOSIROL with water before ingesting.

Method of Preparation

•Pour the entire contents of a single-dose sachet of FOSIROL into a glass of water (90-120 ml) and stir to dissolve.

•Do not use hot water. FOSIROL should be taken immediately after dissolving in water.

Fosfomycin: Probable Place in Therapy

EAU Guidelines Recommendations

• 3 g every 10 daysRecurrent UTI

• 3 g single dose

Asymptomatic bacteriuria and cystitis during

pregnancy

•FOSFOMYCIN is contraindicated in patients with a known hypersensitivity to the drug.

Contraindications

Warnings and PrecautionsDo not use more than one single dose of FOSFOMYCIN to treat a single episode of acute cystitis, it may increase the incidence of adverse events.

•Drug Interactions

Metoclopramide: When metoclopramide (a drug that increases gastrointestinal motility) is co-administered with fosfomycin trometamol, it lowers the serum concentration and urinary excretion of fosfomycin.

Cimetidine: Cimetidine does not affect the pharmacokinetics of fosfomycin when co-administered with fosfomycin trometamol.

Warnings and Precautions

•Renal ImpairmentDosage adjustment is not necessary.

•Hepatic Impairment No specific dosage recommendations can be made.

•Pregnancy (Category B)FOSIROL should be used during pregnancy only if clearly needed.

•Pediatric UseThe safety and efficacy of fosfomycin in children aged 12

years and under have not been established.

Common Side Effects

•Most frequently reported side effects are1

diarrhoea (most common)headache vaginitis nausea dizziness

•Fosfomycin is generally well tolerated.2

1. Drugs @ FDA as assessed on 4/9/142. Infectious Diseases in Clinical Practice 2001; 10: 255–260

Take Home Massages

UTI is the common infection occurring in young women.

The most common presentation in young non-pregnant women is acute uncomplicated cystitis.

The recommended treatment for acute uncomplicated cystitis is short course with antimicrobials like:

Fosfomycin Nitrofurantoin Pivmecillinam

The most common pathogen causing UTI is E.coli.

Take Home Massages

• Fosfomycin is a broad-spectrum bactericidal antibiotic which is active against both Gram-positive and Gram-negative bacteria.

• Fosfomycin should be considered as first-line treatment of acute uncomplicated cystitis due to following unique features:

High susceptibility against E.coli Optimal urinary concentration Least resistance even after long-term usage Established efficacy and safety Single-dose therapy with better patient compliance

Take Home Massages

•Single-dose fosfomycin trometamol had similar clinical and bacteriological efficacy to 3- to 7-day regimens of ciprofloxacin, norfloxacin, perfloxacin, nitrofurantoin, cephalexin, trimethoprim, pipemidic acid, ofloxacin, co-trimoxazole and amoxicillin in women with uncomplicated lower UTIs.

•The recommended dose of FOSFOMYCIN is single 3 g dose.

One can really make difference…..

Thank you

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SINGLE DOSE treatment of URINARY TRACT INFECTION in women, Dr Sharda jain , Dr. jyoti Agarwal , Dr....

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