Recurrent Genitourinary Infections Nalini Rao, MD, FACP, FSHEA,FIDSA Chief, Infectious Diseases UPMC Shadyside Clinical Professor of Medicine and Orthopedics University of Pittsburgh School of Medicine 2013

URINARY TRACT INFECTIONS (UTI) EPIDEMIOLOGY Occurrence varies with age and sex Males: Without urologic abnormalities…. Rare until age 50 Under 50…. Risk factors: HIV, Homosexuality; lack of Circumcision Over 50…. Risk factors: prostatic hypertrophy; obstruction; instrumentation

Females: Infreq. school girls…. Common after adolescence Risk factors: • Sexual intercourse • Use of diaphragm and/or spermicide • Pregnancy Postmenopausal women…. Increased risk due to Estrogen lack (altered vaginal flora) Bacteriuria exceeds 40%

URINARY TRACT INFECTIONS (UTI) ETIOLOGY Bacterial

1.Acute uncomplicated >90% E. coli 10% S. saprophyticus, Klebsiella, Proteus 2.Recurrent Mostly E. coli Proteus, Klebsiella, Enterococci, Enterobacter (Due to increased antibiotic resistance) 3.With calculi Proteus, Klebsiella, Enterococci, S. aureus

URINARY TRACT INFECTIONS (UTI) ETIOLOGY 4. With urologic manipulations/obstruction Proteus, Klebsiella, Enterbacter, Serratia, Pseudomonas, Enterococci, S. aureus 5. Bacteremic infection: S. aureus Other 1. Adenovirus: hemorrhagic cystitis 2. Ureaplasma, mycoplasma: uncertain Candida (catheters and complicated)

URINARY TRACT INFECTIONS (UTI) PATHOGENESIS

1. Interaction between infecting strain, inoculum size, host defense a. Urovirulent clones of E. coli Fimbriae or pili (adherence) Antiphagocytic (K antigen) Hemolysin (cytotoxic) Aerobactin (iron scavenging) Serum resistance (survival)

b. Host defense Flushing and diluting effects of voiding Bladder mucopolysaccharide layer…. Tamm-Horsfall protein; Lactoferrin; SIgA Antibacterial properties of urine…osmolality; pH; organic acid Prostatic secretions Leukocytes in bladder wall…. Cytokines Immune system…. Humoral/cell-mediated

URINARY TRACT INFECTIONS (UTI) PATHOGENESIS 2. Renal parenchymal infection: ascending > bacteremic

3. Other: age and sex; pregnancy; obstruction; neurogenic bladder; Vesico-ureteral reflux; diabetes; diaphragm and/or spermicide use; blood group and non-secretor status

Recurrent Urinary Tract Infections (RUTI)

• Recurrent Urinary Tract Infection refers to three or more symptomatic episodes over a twelve month period • Affects 25% - 30% of patients • RUTI …. Reinfection …. New infection Relapse …. Same organism re-grown < 2 weeks of initial treatment Re-infection is more common than relapse accounts for 80% of RUTI

Recurrent Urinary Tract Infections (RUTI)

Bacteriology •E. coli 70% - 95% •Staphylococcus saprophyticus 15% - 25% •Hospital-acquired infections …. polymicrobial and multi-drug resistant complicated by underlying host factors

Recurrent Urinary Tract Infections (RUTI) RISK FACTORS 1. Healthy/premenopausal women 2. Menopausal women A. Healthy post menopausal women between 50 and 70 years B. Elderly institutionalized women including many who were catheterized

Recurrent Urinary Tract Infections (RUTI) RISK FACTORS FOR HEALTHY PREMENOPAUSAL WOMEN • • • • • •

Sexual Intercourse Use of contraception (spermicides, diaphragm) Antimicrobial use Estrogen Genetics Distance of urethra from anus

Recurrent Urinary Tract Infections (RUTI) RISK FACTORS FOR POSTMENOPAUSAL WOMEN •Estrogen deficiency •Urogenital surgery •*Incontinence …. Urinary/fecal •Presence of cystocele/rectocele •High post-void residual •*Non-secretor status •*Prior UTI •Perineal hygiene •Diabetes mellitus •Immunosuppression/Transplantation •Indwelling catheter * Independent risk factors

Ref. Stamm and Raz CID 1999

Recurrent Urinary Tract Infections (RUTI) In Men 1. 2. 3. 4. 5. 6. 7. 8.

Enlarged prostate  Residual  Prostatic antibacterial activity Neurogenic bladder Diabetes mellitus Low serum albumin Medications Bowel incontinence

Prostatitis - Varied complaints of Lower UT - 50% of adults … during their life time - 25% of office visits of men Pathogenesis - Ascending infection - Uropathogenic bacteria - Decreased zinc conc. in prostatic fluid (zinc containing polypeptide … prostatic antibacterial factor) - Decreased local IgG levels N. Rao

URINARY TRACT INFECTIONS (UTI) IN DIABETES Epidemiology Higher rate [16% - 19%] bacteriuria Four-fold increase in pyelonephritis Two-fold increase in renal abscesses Increased incidence of renal carbuncle Increased incidence of nosocomial Infections

URINARY TRACT INFECTIONS (UTI) IN DIABETES COMPLICATIONS

%

Emphysematous pyelonephritis

72

Emphysematous pyelitis

50

Emphysematous cystitis

80

Perinephric abscess

36

Papillary necrosis

57

Metastatic infection

12

Catheter – associated UTI 1.CA UTI: symptoms ± 103 cfu/ml of a single bacterial strain while catheter is in place or removed within 48 hours 2Symptoms include chills, fever, altered mental status, lethargy, flank pain, acute hematuria or pelvic pain 3.Patients with spinal cord injury – bladder spasm and sense of unease 4. Pyuria is not diagnostic of CA UTI

Catheter – associated UTI Limiting use of urinary catheter 1. Use only if necessary 2. Not for incontinence 3. Physician order 4. Bladder scan 5. Quality indicator Discontinuation of the catheter 1. Remove catheter as soon as feasible 2. Electronic physician reminder 3. Automatic STOP order Ref. IDSA Urinary Catheter Guidelines – CID 2010:50 March

Catheter – associated UTI Alternatives to in-dwelling catheter 1.Intermittent catheterization 2.Suprapubic catheter Data insufficient if one better than the other Intermittent catheterization 1.Clean catheter vs Sterile single-use catheter …..insufficient data 2. Hydrophilic catheters not recommended 3. Portable bladder scan …..insufficient data Ref. IDSA Urinary Catheter Guidelines – CID 2010:50 March

Catheter – associated UTI Prevention 1.Insertion of catheter – aseptic/sterile equipment 2.Closed catheter system 3.Antimicrobial-coated catheter ….insufficient data 4.Routine catheter change ….insufficient data 5.Antimicrobials in drainage bag – not recommended 6.Prophylactic antibiotics for catheter removal or replacement – not recommended Ref. IDSA Urinary Catheter Guidelines – CID 2010:50 March

Catheter – associated UTI Prevention 7. Systemic antibiotics – not recommended 8. Methenamine salts should not be routinely used 9. Cranberry products should not be routinely used 10. Enhanced meatal care with betadine, antibiotics not recommended

Ref. IDSA Urinary Catheter Guidelines – CID 2010:50 March

Recurrent Urinary Tract Infections (RUTI) TREATMENT 1. 2. 3. 4. 5. 6. 7. 8.

Sufficient fluid intake Perineal care Treat incontinence Indwelling catheter Estrogen therapy Cranberry products Methenamine salts Prophylactic antibiotics

Recurrent Urinary Tract Infections (RUTI) ESTROGEN DEFICIENCY • Leads to increase in pH and fall in no. of lactobacilli • Increased ligament laxity and genital prolapse • Alteration of the genitourinary collagen metabolism

Recurrent Urinary Tract Infections (RUTI) ESTROGEN REPLACEMENT FOR RUTI 1.Raz and Stamm – DBPCT (CID 1999) Topical estrogen vs placebo Results: 0.5 vs 5.9 episodes/patient p value < 0.001 Lactobacilli appeared in 61% of estrogen group p value < 0.001 Mean pH decrease from 5.5 to 3.6 Eriksen (Am J Ob Gyn 1999) Estrodiol-releasing silicone ring Decreased recurrences and increased intervals p value = 0.008

Recurrent Urinary Tract Infections (RUTI) INDICATIONS AND CONTRAINDICATIONS FOR ESTROGEN THERAPY Indications Oral therapy, young postmenopausal women

Disadvantages Endometrial carcinoma Breast carcinoma Thromboembolic disorders Liver disease High blood pressure Diabetes mellitus Gall stones

Vaginal topical therapy, elderly women (≥ 60 years)

Difficulties in vaginal therapy Physical limitations Tremor S/P Cerebrovascular accident Dementia Psychological problems: Education/cultural problem

Recurrent Urinary Tract Infections (RUTI) Cranberry products Cochrane review (Jepson RG, Craig JC 2009) Identified 10 RCT, four included in the meta analysis Demonstrated …. Cranberry significantly reduced Incidence of UTI in one year compared to placebo. More effective in younger adult females with RUTI than older people Cranberry juice can potentiate warfarin

Drug Regimen for Prostatitis Subset

Acute prostatitis

Ch. Prostatitis

Usual Pathogen

Preferred IV Rx

Alternate IV Rx

Enterobaceriacae

Quinolone q1224 - 2wk Ceftriaxone 1G q24 – 2wk

TMP/SMX 2.5mg/kg q6 – 2wk Aztreonam 2G q8 – 2wk

Quinolone q1224 2wk TMP/SMX 1DS Q12 2wk Doxycycline 100mg q12 2wk

IV Rx N/A

Quinolone P.O q12-24 1-3 months Doxycycline 100mg q24 TMP/SMX 1DS q12 1-3 m

Enterobacteriacae IV Rx N/A

P.O switch

Drug Regimen for Epididymitis Subset

Usual Pathogen

Preferred IV Rx

Alternate IV Rx

P.O. switch

Young males

C. trachomatis

Doxycycline Quinolone q12 200mg q12 X3d. 24 X7d Then 100mg q12 X4d

Doxycycline 100 q12 X7d Azithromycin 1G X 1dose Cipro 500mg bid X7d

Elderly male

Pseudomonas aeruginosa

Cefepime 2G q8 X10d Meropenem 1G q8 X10d

Cipro 750 mg P.O. q12 X10d

Ch. Epididymitis

MTB, Blastomyces dermatiditis

Treat as pulm TB Treat as pulm blastomycosis

Cipro 400mg q12 X10d Pip/Tazo 4.5G q8 X10d

Fosfomycin • Inhibits bacterial cell wall synthesis • Coverage includes many gram +/- organisms, including most strains of E coli (>90% susceptible) and Enterococcus faecalis – Not reliably active against Pseudomonas • No cross-resistance between fosfomycin and other antibiotics • Peak urine concentrations ~4000 mg/L, decreasing to 50 mg/L - after 36-48 hours • Non-toxic • Dose: 3G po X 1 Patel SS, et al. Drugs 1997;53.

Treatment of Multidrug-Resistant Urinary Pathogens Vancomycin-Resistant Enterococci Indication Cystitis

Pyelonephritis/ Systemic Disease

Preferred 1) Ampicillin or amoxicillin (if susceptible) 2) Nitrofurantoin or doxycycline (if ampicillin resistant)

1) Ampicillin +/- gentamicin (if susceptible) 2) Daptomycin (if ampicillin resistant)

Alternatives Fosfomycin Linezolid Daptomycin

Linezolid Quinupristin/Dalfopristin

Heintz BH, et al. Pharmacotherapy 2010;30:1136-1149

Treatment of Multidrug-Resistant Urinary Pathogens Extended-Spectrum β-Lactamase Producing Organisms Indication

E. coli

Klebsiella / other Enterobacteriaceae

Cystitis

• • • • •

Fosfomycin Nitrofurantoin Ertapenem Amp/Sulb or Amox/Clav Piperacillin/tazobactam

• Ciprofloxacin • Ertapenem • ??? Data on other therapies

Pyelonephritis/ Systemic Disease

• • •

Ertapenem ?Ampicillin/Sulbactam ?Piperacillin/Tazobactam

• Ciprofloxacin • Ertapenem

Rodriguez-Bano J, et al. Arch Intern Med 2008;168:1897-1902 Rodriguez-Bano J, et al. Clin Infect Dis 2012;54:167-174

Treatment of Multidrug-Resistant Urinary Pathogens Carbapenem-Resistant Enterobacteriaceae (a.k.a KPC) Indication Cystitis

Pyelonephritis/ Systemic Disease

Potential Options • • • • •

Gentamicin/Tobramycin ??? Fosfomycin ??? Nitrofurantoin ??? Colistin ??? Doxycycline / Tigecycline

•

Doripenem + Colistin +/- Tigecycline or Gentamicin

Satlin MJ, et al. Antimicrob Agents Chemother 2011;55:5893-5899 Tumbarello M, et al. Clin Infect Dis 2012;55:943-950 Qureshi ZA, et al. Antimicrob Agents Chemother 2012;56:2108-2113

Antibiotic Dosing in Renal Failure Agent

Cystitis

Pyelonephritis/ Systemic Disease

Dose Adjustment for Renal Dysfunction

Amp/Sulb Aztreonam Cefuroxime IV Cefuroxime PO Ceftriaxone Cefepime Ciprofloxacin IV Ciprofloxacin PO Gentamicin Pip/Tazo Tobramycin Meropenem

1.5g IV Q6H 1g IV Q8-12H 750mg IV Q8H 500mg PO Q12H 1g IV Q24H 1g IV Q12H 200mg IV Q12H 250mg PO Q12H 1mg/kg IV Q8H 4.5g IV Q12H 1mg/kg IV Q8H 0.5g IV Q8H

3g IV Q6H 1-2g IV Q8H 1.5g IV Q8H N/A 1g IV Q24H 2g IV Q12H 400mg IV Q12H 500mg PO Q12H 5-7mg/kg IV Q24H 4.5g IV Q6H 5-7mg/kg IV Q24H 1g IV Q8H

Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes

Antibiotic Dosing in Renal Failure Agent

Cystitis

Pyelonephritis/ Systemic Disease

Dose Adjustment for Renal Dysfunction

Daptomycin Doxycycline Fosfomycin Nitrofurantoin TMP/SMX

2-4mg/kg IV Q24H 100mg PO/IV Q12H 3g PO ONCE 100mg PO Q12H 1DS PO Q12H

4-6mg/kg IV Q24H N/A N/A N/A 1DS PO Q12H or 3mg/kg IV Q8H Target trough: 1520mcg/mL

Yes No No Yes – Do not use Yes

Vancomycin

Target trough: 1015mcg/mL

Yes

Candida in the urine

N. Rao

Candidiasis of the Genito-urinary Tract •Presence of yeast in the urine in U/A and urine culture…clinical context • Asymptomatic…observe •Remove indwelling catheter •D/C other antibiotics if feasible

Persistent Candiduria requires Rx * Neonates * Immunocompromised host * Pts undergoing GU instrumentation * Multiple + sites in ICU setting N. Rao

Candidiasis of the Genito-urinary Tract Candida Cystitis Fluconazole Oral flucytocine Amp B…systemic …Local irrigation

C. Glabrata Echinocandin …poor urine conc No prior Azoles exp. High dose Fluconazole

Candida pyelonephritis Candida Prostatitis 20% C. Glabrata Fluconazole L Amp B. Surgical drainage Caspofungin Fungus ball Systemic antifungal therapy N. Rao Surgical intervention

Recurrent Urinary Tract Infections (RUTI) PRACTICE POINTS 1. One in four women will suffer with recurrences 2. E coli is the most common isolated uro-pathogen 3. Verify the diagnosis of RUTI but also find the cause for recurrence 4. UTI is over diagnosed and over treated in older people 5. Diagnosis of UTI requires the presence of new urinary symptoms 6. Topical estrogen is beneficial in older people 7. Cranberry juice is a useful prophylactic adjuvant 8. Chronic urinary catheter should be avoided 9. Chronic antibiotic therapy should be avoided

Thank You!