Rennervate! Old Drug with New Tricks: Fosfomycin in Complicated Urinary Tract Infections

Linda Yang, PharmD PGY2 Infectious Disease Pharmacy Resident

South Texas Veterans Health Care System, San Antonio, TX Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center University of Texas Health Science Center San Antonio

October 14, 2016

Learning Objectives 1. Review definition, pathophysiology and epidemiology of complicated urinary tract infection (UTI)2. Discuss the current therapeutic options for complicated UTI3. Understand the spectrum and pharmacokinetic data of fosfomycin and its possible role as a potential

treatment option for complicated UTI4. Analyze the current literature on using fosfomycin in complicated UTI

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I. Background A. Urinary tract infection (UTI)1-6

1. Definition: infection of any part of the urinary system including kidneys, bladder and urine 2. One of the most common bacterial infections

a. 8.6 million ambulatory care visits in 2007 b. Self-reported incidence in women: 12%

i. Incidence in college women: 0.7 per person-year ii. Incidence in postmenopausal women: 0.07 per person-year

c. Incidence of pyelonephritis: 25 cases per 10,000 women between 15-34 years old d. Ratio of pyelonephritis to cystitis is 1-to-28

3. Most common pathogen: E. coli (75-95%) 4. Risk factors: gender, antibiotic use, spermicides, frequent or recent sexual intercourse, familial

tendency, previous episode of UTI 5. Pathophysiology

a. Three routes: ascending, hematogenous, lymphatic

b. Ascending i. Colonization of periurethral area and migration up the urethra to colonize the bladder

ii. Virulence factors (i.e. fimbrae, flagella, diverse adhesins, siderophores, toxins, polysaccharide coatings, etc.) allow the bacteria to penetrate the bladder and continue to move from the bladder to the kidneys

iii. Ascension through the ureter can lead to infection of the renal parenchyma iv. Prolonged pyelonephritis can lead to complications such as acute kidney injury due to

inflammatory response and/or tubular damage, formation of renal abscess, bacteremia, spread of infection (i.e. prostatitis)

c. Hematogenous i. Metastatic infection secondary to bacteremia

ii. Rarely due to common urinary organisms (i.e. gram negative bacilli) iii. Presentation: renal abscess due to S. aureus bacteremia and/or endocarditis

http://www.pathophys.org/uti/

Figure 1: Ascending Pathway

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d. Lymphatic i. Possibly due to lymphatic connections between ureter and kidneys

ii. Evidence limited to animal studies 6. Complications: pyelonephritis, bacteremia, sepsis, renal damage (i.e. renal abscess, acute kidney

injury, chronic kidney injury, papillary necrosis, hypertension), secondary infection due to spread of infection (i.e. prostatitis), urinary tract cancer, antibiotic resistance, C. difficile colitis

B. Classification4, 6, 7-9

1. Definitions7-10

a. Asymptomatic bacteriuria: presence of bacteria in urine without urinary symptoms b. Cystitis: symptomatic infection of the lower urinary tract c. Pyelonephritis: symptomatic infection of the kidney(s) d. Complicated UTI: symptomatic urinary infection with functional or structural abnormality

2. Asymptomatic bacteriuria7 a. Definition

i. Female: two urine cultures of the same bacteria with counts ≥ 105 cfu/mL ii. Male: one clean-catch urine culture of one bacteria species with counts ≥ 105 cfu/mL

iii. Catheterized: one urine culture with one bacteria species at counts ≥ 102 cfu/mL b. Baseline rates of bacteriuria in patients affect interpretation of studies

i. Pyuria commonly seen in asymptomatic bacteriuria ii. Bacteriuria commonly reported in elderly and catheterized patients

iii. Presence of pyuria with bacteriuria does not always indicate an active infection

UTI

Asymptomatic

Asymptomatic bacteriuria

(ASB)

Symptomatic

Uncomplicated

Cystitis Pyelonephritis

Complicated

Cystitis Pyelonephritis

Catheter-associated UTI (CAUTI)

Figure 2: UTI Classification

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Population Prevalence (%) Healthy, premenopausal women 1-5 Pregnant women 1.9-9.5 Postmenopausal women (age 50-70 years) 2.8-8.6

Elderly persons in the community 10.8-16 (female) 3.6-19 (male)

Elderly persons in long-term care facility 25-50 (female) 15-40 (male)

Intermittent catheter use 23-89 Short-term indwelling catheter use 9-23 Long-term indwelling catheter use 100

c. No treatment recommended in most patient populations i. Treatment in pregnancy is recommend to decrease risk of pyelonephritis, premature

delivery and infants with low birth weight ii. Treatment prior to genitourinary (GU) procedure is recommended to decrease risk of

post-procedure bacteremia and sepsis iii. Treatment in the immunocompromised population specifically the transplant patient

population is debated a. Some experts recommend screening within first six months of transplant b. Patients with poor graft outcome often have symptomatic UTIs c. No reported association between bacteriuria and graft survival

3. Symptoms6, 8, 9

4. Acute uncomplicated cystitis8 a. Definition: symptomatic UTI in females without any functional or structural abnormalities b. Presence of symptoms without vaginal discharge or irritation has a 90% probability of UTI c. Diagnostic tools correlate with infection when used in the presence of symptoms

Cystitis

Frequency

Urgency

Dysuria

Suprapubic pain

Pyelonephritis

Cystitis Symptoms

Costovertebral angle pain

Flank pain

Fever

CAUTI

Difficult to evaluate in the presence of a

catheter

Cystitis ± Pyelonephritis symptoms

Table 1: Asymptomatic Bacteriuria Rates in Different Populations

Figure 3: UTI Symptoms

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Diagnostic Tool Sensitivity (%) Specificity (%) Pyuria 95 71 Bacteria 40-70 85-95 Nitrite or leukocyte esterase 75 82

d. Urine culture is not needed for treatment 5. Uncomplicated pyelonephritis8

a. Definition: symptomatic urinary infection involving the kidneys b. Increased morbidity and mortality risk compared to acute uncomplicated cystitis2 c. Urine culture is recommended to direct treatment

6. Complicated UTI6, 9, 10 a. Definition: symptomatic urinary infection in patients with functional or structural

abnormality of the GU tract (bladder or kidneys) b. Risk factors associated with complicated UTI

i. Structural or functional abnormality a. Enlarged prostate b. Nephrolithiasis c. Congenital anatomical disorder d. Neurogenic bladder

ii. Urinary catheter, stent or nephrostomy iii. GU procedure iv. Renal disease v. Kidney transplant

vi. Diabetes mellitus vii. Immunosuppression

viii. Hospital acquired infection ix. Pregnancy x. Male

xi. Multidrug (MDR) pathogen c. CAUTI

i. Definition: symptomatic urinary infection in patients with indwelling urinary catheters a. Catheter present for > 2 calendar days OR b. Removed less than 48 hr since urine culture

ii. Urine culture is recommended to direct treatment

C. Microbiology of complicated UTI2, 9, 10, 11 1. E. coli is the most common pathogen in both uncomplicated and complicated UTI

a. Less likely to isolate E. coli from male patients b. Broader distribution of pathogens in complicated UTI

Males11 Uncomplicated10 Complicated9, 10 E. coli 30-40% 90% 21-81% Klebsiella spp. 6-12% 8% 1.9-17% Proteus spp. 5-8% 1% 0.9-9.6% Enterobacter ─ 1% 2-9.6% Pseudomonas spp. 3-4% 0% 2-19% Others 45%

(E. faecalis 16-18%) 0% 3-20%

Table 2: Efficacy of Urinalysis4

Table 3: Epidemiology of Urinary Isolates in Specific Populations

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0

20

40

60

80

100

Ciprofloxacin TMP-SMX Ceftriaxone ESBL E. coli

Resi

stan

ce (%

)

Uncomplicated

Complicated

D. Treatment 1. Guideline recommended treatment options for acute uncomplicated cystitis8

Antibiotic Duration (days) Efficacy (%) Nitrofurantoin 100mg BID 5-7 84-95 TMP-SMX DS BID 3 90-100 Fosfomycin 3g for 1 dose 1 91

2. Guideline recommended treatment options for acute uncomplicated pyelonephritis8

Antibiotic Duration (days) Clinical efficacy (%) Microbiological efficacy (%) Ciprofloxacin

± Ceftriaxone or Aminoglycoside

5-7 96 99 Levofloxacin 5-7 ─ ─ TMP-SMX 10-14 83 89

3. Guideline recommended treatment options for CAUTI9 a. Catheter needs to be removed or replaced if duration > 2 weeks b. New urine culture should be collected to determine treatment

Antibiotic Duration Efficacy Acute uncomplicated cystitis regimens 3 days (after removal of catheter) Non-inferior to 10- and 14-day regimens in

patients with intermittent catheterization Levofloxacin 5 days (mild symptoms) 80%; non-inferior to 10 day of ciprofloxacin Broad-spectrum systemic antibiotic

7-14 days depending on resolution of symptoms ─

4. No Infectious Diseases Society of America (IDSA) guidelines for complicated UTI6, 10 a. No recommendations for standard therapy b. Broad-spectrum β-lactams such as cefepime, piperacillin-tazobactam, and carbapenems

used for severe cases with increased concern for MDR organisms c. Ceftriaxone and fluoroquinolones often used to treat mild to moderate cases with limited

concern for multidrug resistance 5. Most frequently prescribed antibiotics from 2002 to 2011 for outpatient treatment of acute

uncomplicated cystitis in the US were fluoroquinolones (50% of all antibiotics prescribed)12 6. Recent FDA warning against the use of fluoroquinolones in the treatment of uncomplicated UTI

states risks outweigh the benefits13

E. Study in Turkey showed increased risk of resistance in complicated UTI (n=226) when compared to uncomplicated UTI (n=288)14

Table 4: IDSA Recommendations for Acute Uncomplicated Cystitis

Table 5: IDSA Recommendations for Acute Uncomplicated Pyelonephritis

Table 6: IDSA Recommendations for CAUTI

Figure 4: Resistance Patterns in Uncomplicated vs. Complicated

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0

20

40

60

80

100

18-64 ≥ 65 18-64 ≥ 65 18-64 ≥ 65

Nitrofurantoin TMP-SMX Ciprofloxacin

Resi

stan

ce (%

)

2003

2012

F. Resistance patterns in urinary isolates 1. Data from 200 institutions included in the Surveillance Network show increasing resistance rates to

common first-line agents in urinary E. coli isolates15

2. Fluoroquinolone resistance in urinary isolates of E. coli has increased over the years a. A study in one health care system shows growing fluoroquinolone resistance in outpatient

urinary E. coli isolates consistent with increased prescribing16 b. CDC data showed an increase in fluoroquinolone resistance from 34.3% in 2012 to 45.2%

in 2014 in CAUTI urinary E. coli isolated in Texas healthcare facilities17 3. Resistance patterns for E. coli at University Hospital and South Texas VA

UH VA Isolates Antibiotic Resistance (%) Isolates Antibiotic Resistance (%) E. coli TMP-SMX 40 E. coli TMP-SMX 37 Ciprofloxacin 36 Ciprofloxacin 34 Nitrofurantoin 9 Nitrofurantoin 9 Ceftriaxone 17 Ceftriaxone 10 Ampicillin 66 Ampicillin 54 Ampicillin-

sulbactam 47 Ampicillin-sulbactam 45

Cefpodoxime 16 Cefpodoxime 16

II. Fosfomycin (Monurol®)18, 19

A. History

1969: Phosphonomycin isolated from Streptomyces fradiae, Streptomyces virichromogens, and Streptomyces wedmorensis by MSD and CEPA in Spain

Further use halted by 2 main issues: (1) oral bioavailability of the calcium salt formulation and (2) discrepancy between in vivo and in vitro results due to lack of standardized testing method (1983)

1996: FDA approved Monurol® for treatment of uncomplicated UTI

2010: IDSA and European Society for Clinical Microbiology and Infectious Diseases (ESCMID) added fosfomycin to the guidelines as first-line agent for treatment of acute uncomplicated cystitis

Figure 6: History of Fosfomycin

Table 7: Local Resistance Patterns

Figure 5: Resistance in E. coli Isolates by Age to First-Line Oral Agents

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B. Mechanism of action

1. Blocks cell wall synthesis by inhibiting first committed step in peptidoglycan synthesis pathway (enolpyruvyl transferase)

C. Spectrum of activity

1. Broad-spectrum activity against both gram positive and gram negative organisms

a. Staphylococci b. Enterococci c. Enteric gram negative including E. coli, P. mirabilis

D. Dosage form: powder sachet (oral administration only)

E. FDA approved indication

1. One dose of 3g for uncomplicated cystitis

Treatment Arm Treatment duration

(days)

Microbiologic eradication rate Clinical success

rate

Outcome (based on microbiologic

eradication rate) 5-11 days

post therapy Study day 12-

21 Fosfomycin 1 630/771

(82%) 591/771

(77%) 542/771

(70%)

Ciprofloxacin 7 219/222 (98%)

219/222 (98%)

213/222 (96%)

Inferior

TMP-SMX 10 194/197 (98%)

194/197 (98%)

186/197 (94%)

Inferior

Nitrofurantoin 7 180/238 (76%)

180/238 (76%)

183/238 (77%)

Equivalent

2. Dose adjustment: none recommended

F. Adverse drug reactions 1. Very well tolerated 2. Most common: diarrhea, nausea

G. Pregnancy category: B

H. Drug interactions: limited potential for interaction

I. MIC breakpoints

1. Must supplement media with glucose-6-phosphate 2. Agar dilution is the only approved method in US

S I R Annotations FDA ≤ 64 128 ≥ 256

CLSI Enterobacteriaceae ≤ 64 128 ≥ 256 For E. coli urinary tract isolates only Enterococcus ≤ 64 128 ≥ 256 For E. faecalis urinary tract isolates only

EUCAST Enterobacteriaceae ≤32 ─ >32 For uncomplicated UTI only

3. Based on MIC50 and MIC90: expect high rates of resistance in Pseudomonas spp. and Acinetobacter spp.

Table 8: Comparison of RCTs for Acute Uncomplicated Cystitis

Table 9: Breakpoints 19, 20, 21

Figure 7: Molecular Structure

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Organisms Package Insert Perdigao-Neto et al. Kucer’s Range Isolates (n) MIC50 MIC90 Isolates (n) MIC50 MIC90 E. coli 0.5-2 ─ ─ ─ 51 1 4 Enterococcus spp. ─ 10 64 64 41 32 64 E. faecalis 32-128 ─ ─ ─ ─ ─ ─ VRE (E. faecium) ─ ─ ─ ─ 75 32 48 Klebsiella spp. ─ ─ ─ ─ 30 16 32 P. aeruginosa 2-8 15 256 256 ─ 128 256 Acinetobacter spp. ─ 42 64 128 10 128 128 Enterobacter spp. ─ 10 64 64 45 16 32 P. mirabilis ─ ─ ─ ─ ─ 4 >128

J. Pharmacokinetics 1. Absorption

a. Bioavailability: 34% - 58% b. Food does not affect absorption (fasting 37% vs fed 30%)

2. Distribution a. Protein binding < 3% b. Volume of distribution: 136.1 ± 44.1 L

i. Adults: 2.4 L/kg ii. Elderly: 1.5 L/kg

c. Tissues: kidney, bladder, prostate, seminal vesicles 3. Metabolism – none reported 4. Excretion

a. Unchanged 38% in urine and 18% in feces b. Mean renal clearance rate: 6.3 ± 1.7 L/hr c. Mean total body clearance: 16.9 ± 3.5 L/hr d. t1/2: 5.7 ± 2.8 hr (elderly: 8 hr; renal impairment: up to 50 hr)

5. Serum and urine concentrations 1. Fosfomycin trometamol should not be used in systemic infections 2. Fosfomycin concentrates well in the urine 3. Early pharmacokinetics data for fosfomycin trometamol is based on 50 mg/kg dosing 4. Urine and serum concentrations were evaluated in 30 healthy patients with average

weight of 66kg24

Time Serum (mcg/mL) Urine (mcg/mL) 3 25 ± 4 2428 ± 466 6 17 ± 3 1906 ± 172 12 7 ± 2 1023 ± 228 24 2 ± 1 490 ± 116 36 ─ 168 ± 35 48 ─ 31 ± 10

K. Pharmacodynamics25

a. Bactericidal and concentration-dependent i. Time-dependent killing has been exhibited with S. aureus

ii. Concentration-dependent killing exhibited with S. pneumoniae, E. coli, and P. mirabilis

Table 10: MIC50 and MIC90 19, 22, 23

Table 11: Serum and Urinary Concentrations after 3g Dose

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0

20

40

60

80

100

FQ-S FQ-R SXT-S SXT-R NIT-S NIT-R

Isol

ates

(%)

Klebsiella spp.

FOS-R

b. In vitro antibiotic activity in E. coli and P. mirabilis i. Bactericidal activity of E. coli cultures occurred at ≥ 4 x MIC

ii. Sterilization of P. mirabilis cultures occurred at ≥ 8 x MIC iii. Post antibiotic effect averages 3-4 hours

L. Susceptibility in MDR isolates

a. Ranges from 75 to 100%26-28 b. Study in Boston found fosfomycin susceptibility of 79.4% in MDR urinary isolates26

Isolates (n=204) Susceptibility (%) E coli (n=120) 95.8 Klebsiella spp. (n=71) 54.6

c. High resistance rates for fluoroquinolone and TMP-SMX for E. coli with high susceptibility rates for fosfomycin in these isolates26

M. Summary of the advantages in using fosfomycin in UTI 1. Achieves high concentrations in the urine 2. Easy oral outpatient regimen 3. Favorable safety profile 4. Activity against common urinary organisms 5. Majority of E. coli isolates are susceptible including ESBL-producers

III. Literature Review

A. First study with subpopulation of complicated UTI patients showed possible efficacy29 1. Multicenter, open, non-controlled study looking at fosfomycin in UTI 2. 365 patients treated with fosfomycin either 3g once or 3g every other day for 3 doses

Table 12: Fosfomycin Susceptibility in 204 MDR isolates

Figure 8: Association of Fosfomycin Resistance to First-Line Agent Resistance in E. coli Isolates

0

20

40

60

80

100

FQ-S FQ-R SXT-S SXT-R NIT-S NIT-R

Isol

ates

(%)

E. coli

FOS-R

Figure 9: Association of Fosfomycin Resistance to First-Line Agent Resistance in Klebsiella spp.

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Population (n=365) Complicated UTI (n=49) Male (%) 23% (84) 41% (20) Inpatient (%) 61% (221) 96% (47) Multiple Doses (%) 46% (167) 57% (28) Pregnant (%) 4% (13) 0% (0)

3. Cure rate for complicated UTI was 82.1% for multiple doses and 57.1% for single dose 4. Fosfomycin susceptibility in E. coli estimated at 94.7% and in other pathogens at 76.6% 5. Several limitations with study design, definition of “cure”, selected risk factors, heterogeneous

population, lack of baseline characteristics

B. Clinical Studies28, 30-33 Sastry S, Clarke LG, Alrowais H, Querry AM, Shutt KA, Doi Y. Clinical Appraisal of Fosfomycin in the Era of Antimicrobial Resistance. Antimicrob Agents Chemother. 2015;59(12):7355-61. Objective To elucidate recent trends in the use of fosfomycin, its indications, and the clinical outcomes of

hospitalized patients treated with this agent Design Single center, retrospective cohort study Population Hospitalized patients who received fosfomycin between Jan 2009 to Dec 2013

Inclusion • Admitted to acute care unit • ≥ 1 dose of fosfomycin during hospitalization Fosfomycin-defined Inclusion • Presumed or confirmed UTI per physician Exclusion • Negative urine culture • Negative urinalysis • Concurrent antibiotics

National Healthcare Safety Network (NHSN) defined Inclusion • Positive urine culture • NSHN criteria (Appendix A)

Endpoints • Primary: clinical response after 48 hr of treatment • Secondary: recurrence within 30 days after receipt of fosfomycin, adverse events, 30-day in-

hospital mortality rates Statistics • Univariate logistic regression for predictors of failure at 48 hr

• Multivariate analysis on variables with P ≤ 0.2 using stepwise logistic regression • Two-tailed P value of ≤ 0.05 considered statistically significant

Baseline Characteristics

All (n=537) Fosfomycin-treated (n=119) NHSN-defined (n=89) Male 15% (81) 10% (12) 18% (16) Catheter 30% (162) 29% (34) 34% (30) Transplant 5% (25) 3% (4) 6% (5) Immunosuppressed 18% (99) 19% (23) 17% (15) Recent antibiotics ─ 30% (36) 40% (32) Concurrent antibiotics ─ 0% (0) 22% (20) Positive culture 68% (363) ─ 100% (89) E. coli 52% 41% (49) 56% (50) MDR 23% 20% (24) 40% (36) ESBL ─ 6% (7) 9% (8) Complicated UTI ─ 77% (92) 81% (72)

Age

18-34 ─ 8% (9) 11% (10) 35-49 ─ 8% (10) 13% (12) 50-74

84% (451) 43% (51) 47% (42)

≥ 75 41% (49) 28% (25) ICU 19% (101) 20% (24) 17% (15) Charlson 0-5 57% (305) 53% (63) 64% (57)

Table 13: Baseline Characteristics

Table 14: Baseline Characteristics

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6-10 40% (215) 40% (48) 33% (29) ≥ 11 3% (15) 5% (6) 2% (2)

Hospital Acquired 40% (214) 45% (53) 52% (46) Single Dose ─ ─ 97% (86)

Results All 100 randomly selected ESBL-producing E.coli isolates were susceptible to fosfomycin

Failure Success All fosfomycin-treated (n=239) 12% (30) 88% (209) Fosfomycin-treated without indeterminate outcomes (n=119) 25% (30) 75% (89)

NHSN-defined (n=89) 10% (9) 90% (80)

• All patients with complicated UTI in the NHSN-defined group who failed therapy received a single dose of fosfomycin

• Recurrence 4.3% (23/537) • Adverse events 2% (11/537): all mild and GI related • In-hospital mortality 1.9% (10/537): none attributed to treatment

Fosfomycin-treated (n=92) NHSN-defined (n=72) Rate of Success in complicated UTI 72.8% (67) 87.5% (63)

Author’s Conclusion

• Fosfomycin was used mainly to treat uncomplicated UTI • Clinical outcomes were favorable in both groups

Strengths • NHSN-defined UTI group o Positive urine culture o Strict criteria

• High percentage of patients with complicated UTI (~80% in both groups) Limitations • Study design (retrospective, single center)

• Lack of comparator • Not able to extract baseline characteristics for complicated UTI • Portion of patients in NHSN-defined group on concurrent antibiotics • Fosfomycin susceptibility not tested on isolates • Majority used one 3g dose • Definition of success include cured and indeterminate • Microbiological cure not assessed • Unknown proportion of patients in NHSN-defined group with systemic signs or symptom

Take Home Points

• Lower rate of success in complicated UTI compared to acute uncomplicated cystitis o Success rate still > 80% with 1 dose of 3g in complicated UTI o Success was measured only by resolution of clinical response

• All 9 patients who failed therapy in NHSN group had complicated UTI o All of these patients only received one dose of fosfomycin o Only one of these cases attributed failure due to fosfomycin therapy

Qiao LD, Zheng B, Chen S, et al. Evaluation of three-dose fosfomycin tromethamine in the treatment of patients with urinary tract infections: an uncontrolled, open-label, multicentre study. BMJ Open. 2013;3(12):e004157. Objective To evaluate the clinical and microbiological efficacy and safety of three doses of 3g fosfomycin

tromethamine administered orally to treat lower urinary tract infections Design Multicenter, prospective, uncontrolled, open-label study Population Outpatient visits at an urology department in one of 12 hospitals in China from Jan 2011 to Dec 2011

Inclusion • Age between 18 and 70

Exclusion • Isolate resistant to fosfomycin

Table 15: Clinical Success

Table 16: Clinical Success in Complicated UTI

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• Acute uncomplicated cystitis, recurrent lower UTI or complicated lower UTI

• Allergy to study drug • Fever • Grade 3 or 4 cardiac insufficiency • Pregnancy • Pyelonephritis • Renal failure • Liver disease • WBC < 2x109 • Receipt of other antibiotics < 72 hr • Late stages of malignant tumors • Long-term use of hormones or

immunosuppressants • History of epilepsy or CNS disorders • Severe diarrhea

Intervention Fosfomycin tromethamine powder 3g every other day for 3 doses Endpoints Efficacy: clinical, microbiological and overall efficacy at day 15

• Clinical – symptoms and signs designated as “cured,” “improved” or “ineffective” • Microbiological – bacteria in urine culture designated as “eradicated,” “persistence,”

“replacement” or “reinfection” • Overall – combination of the clinical and microbiological efficacy divided into 4 categories

Safety: adverse events reported by severity (patient assessed) and relatedness (physician assessed) Statistics • Ratio and numerical data reported for efficacy and safety data respectively

• Per protocol (PPS) patients considered the primary analysis population Baseline Characteristics

Half of the patients enrolled had positive urine culture and one-fifth had complicating factors

Organisms (n=198) MIC50 MIC90 Susceptibility (%)

E. coli (n=41) 0.125 5 95.1 ESBL E. coli (n=46) 0.125 128 87 K. pneumoniae (n=9) 1 32 100

Proteus spp. (n=9) 1 >256 55.6 CoNS (n=26) 0.25 32 96.2 E. faecalis (n=15) 32 32 100

Variables Prevalence Male 29% (105/335) Age 49.91 ± 16.61 Antibiotics < 72 hr before enrollment 13% (43/335)

Diabetes 7% (24/335) Complicated UTI 20% (67/335) Positive culture 55% (198/356) Positive culture in complicated UTI 46% (31/67)

Results Overall efficacy rate for acute uncomplicated cystitis was 95% and for recurrent lower UTI was 78%

Complicated UTI Clinical efficacy 63% (42/67) Microbiological efficacy 84% (23/31) Overall efficacy 65% (20/31)

Author’s Conclusion

Three 3g doses of fosfomycin were effective and well-tolerated in treatment of acute uncomplicated cystitis, recurrent lower UTI or complicated lower UTI

Strengths • Multicenter, prospective study • Tested fosfomycin susceptibilities • Used multiple dose dosing regimen

Limitations • Lack of comparator • Only half the patients had positive urine culture • Limited baseline characteristics

o Did not report the risk factors for complicated UTI in this population o No pertinent labs reported

Table 17: Epidemiology of Positive Urine Culture32 Table 18: Baseline Characteristics

Table 19: Efficacy in Complicated UTI

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• Used the same dose in acute uncomplicated cystitis and complicated lower UTI Take Home Points

• Consider as alternative treatment for culture-directed treatment with overall efficacy rate of about 65% with susceptible isolates

o May consider using this as salvage therapy in stable outpatient population who developed a mild complicated UTI without any systemic signs of infection

Neuner EA, Sekeres J, Hall GS, Van duin D. Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms. Antimicrob Agents Chemother. 2012;56(11):5744-8. Objective To describe the microbiological outcomes of UTIs due to MDR pathogens treated with fosfomycin Design Single center, retrospective study Population Hospitalized patients from Jan 2006 to Dec 2010 in Ohio

Inclusion • ≥ 18 years old • ≥ 1 dose of fosfomycin • MDR pathogen in urine culture with fosfomycin susceptibility • Allowed concomitant antibiotics

Intervention Fosfomycin 3g per dose at 2.9 ± 1.8 doses Endpoints Rate of microbiological cure Statistics • Student t test and Mann-Whitney U test were used to compare continuous variables between

patients with microbiological cure and patients with microbiological failure • Fisher exact and X2 tests used to compare categorical variables • All tests were 2-tailed

Baseline Characteristics

Combination therapy in 27% (11/41)

Organism (n)

MIC50 (µg/mL)

MIC90 (µg/mL)

Susceptible (%)

CR-KP (13) 32 64 92 P. aeruginosa (8) 8 256 75 VRE (7) 64 64 86 ESBL (7) 1 16 100 E. coli (5) 1 128 80 Other (4) 75

Variable Prevalence (n=41)

Age, mean ± SD 62 ± 13 Male, % (n) 45 (19) Hospital LOS, median days (range) 14 (3 – 166) Diabetes, % (n) 59 (24) CKD, % (n) 46 (19) Hem/Onc, % (n) 15 (6) SOT, % (n) 37 (15) Immunosuppression, % (n) 51 (21) Charlson, mean (range) 4 (0 – 8) Foley catheter, % (n) 63 (26) History of recurrent UTI, % (n) 24 (10) Urological surgery, % (n) 15 (6) Neurogenic bladder, % (n) 12 (5) Ureteral stent, % (n) 10 (4) ≥ 1 complicating factor, % (n) 80 (33) UA only, % (n) 17 (7) Symptoms only, % (n) 12 (5) UA + Symptoms, % (n) 68 (28)

Table 20: Microbiology and Fosfomycin Susceptibility Table 21: Baseline Characteristics

CR-KP: carbapenemase-producing K. pneumoniae; ESBL: extended spectrum beta-lactamase

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Figure 10: Susceptibility and Cure by Organism

Results • No statistically significant differences in the number of doses between the two groups (cure 3.3 ± 1.9 vs failure 2.4 ± 1.5)

• Microbiological cure: 59% (24/41) • Microbiological failure: 41% (17/41)

o Relapse: 10 o Reinfection: 7

• Cure rates varied by susceptibility o MIC ≤ 64 µg/mL: 60%

(21/35) o MIC 128 µg/mL: 100% (3/3) o MIC ≥ 256 µg/mL: 0% (0/3)

• Microbiological cure in complicated UTI: 52% (17/33)

• Cure in patients with foley: 58% (15/26) • Microbiological cure in combination therapy: 53% (9/17) • Only statistical significant difference between cure and failure was in the SOT population • Resistance developed in 3 patients with CR-Kp (all were kidney transplant patients with stents)

Author’s Conclusion

• Overall the rate of microbiological cure was lower than the in vitro susceptibility o CR-Kp had the biggest divergence in microbiological response and in vitro susceptibility

• Use caution when using fosfomycin to treat certain patient populations: SOT and ureteral stents • Fosfomycin resistance may develop

Strengths • Included variety of MDR organisms • In vitro susceptibilities are consistent with those reported in literature • Big portion of patient population have complicating risk factor

Limitations • Study design (retrospective, single center, not randomized, no comparator) • Only looked at microbiological cure (not a good surrogate endpoint for efficacy) • Portion of patients had asymptomatic bacteriuria • Small sample size • Heterogeneous patient population • Portion of patients did not have source control • No CLSI standards for susceptibility on several of these organisms (extrapolated breakpoints for

other Enterobacteriaceae and Pseudomonas spp. from E. coli and E. faecalis breakpoints) Take Home Points

• Caution using fosfomycin to treat complicated UTI in SOT patients or patients with ureteral stents especially if source control is not achieved

• Fosfomycin has high cure rates for certain MDR organisms (ESBL-producing E. coli and K. pneumoniae, VRE and other MDR E. coli)

• Caution using fosfomycin to treat CR-Kp and P. aeruginosa UTIs Senol S, Tasbakan M, Pullukcu H, et al. Carbapenem versus fosfomycin tromethanol in the treatment of extended-spectrum beta-lactamase-producing Escherichia coli-related complicated lower urinary tract infection. J Chemother. 2010;22(5):355-7. Objective To compare the effects of fosfomycin and carbapenems in the treatment of ESBL-producing E. Coli-

related complicated lower urinary tract infection Design Single center, observational, prospective study Population Patients from one hospital system (inpatient and outpatient) in Turkey from Mar 2005 to Jan 2006

Inclusion • Age > 18 years

Exclusion • Fever

0

20

40

60

80

100

Microbiological Cure Susceptible

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• Urinary symptoms (dysuria, problems with frequency, urgency in passing urine)

• > 20 leukocytes/mm3 in urine • ESBL-producing E. coli sensitive to fosfomycin

and carbapenem with > 105 cfu/mm3

• Leukocytosis

Intervention Carbapenem Meropenem 1g q8h or Imipenem-cilastatin 500mg q6h for 14 days

Fosfomycin (FT) Fosfomycin tromethamine powder 3g every other night for 3 doses

Endpoints • Clinical success: resolution of symptoms • Microbiological success: sterile urine culture 7-9 days after end of treatment

Statistics • Pearson X2, Fisher’s exact test and Student’s t-test used for statistical comparison • P < 0.05 considered statistically significant

Baseline Characteristics

• No statistically significant differences between the two groups

• More patients in the fosfomycin group were catheterized and male

Carbapenem (n=20) FT (n=27)

Male, % (n) 35 (7) 48 (13) Age, mean ± SD 57.5 ± 20.7 57.5 ± 15.3 Complicating factor, mean ± SD

1.8 ± 0.7 1.7 ± 0.5

>1 factor, % (n) 65 (13) 70 (19) Indwelling catheter, % (n) 40 (8) 52 (14)

Complicating factors Prevalence, % (n)

Permanent/intermittent catheterization 46.8 (22)

History of urologic operation 21 (10) Neurogenic cystitis 21 (10) Renal failure 19.1 (9) Malignancy 17 (8) Prostate hypertrophy 10.6 (5) Renal transplant 10.6 (5) Diabetes mellitus 8.5 (4) Nephrolithiasis 6.3 (3) Gynecologic problems 4.3 (2) Neutropenia 4.3 (2) Congenital anatomical disorder 4.3 (2)

JJ catheter 2.1 (1) Deteriorated immunologic status 2.1 (1)

Results FT (n=27) Carbapenem (n=20) p-value Microbiological response 59% (16) 80% (16) > 0.05 Clinical response 78% (21) 95% (19) > 0.05 Reinfection 6% (1/16) 6% (1/16) > 0.05 Relapse 6% (1/16) 6% (1/16) > 0.05

• Microbiological and clinical response not statistically different but numerically inferior in the fosfomycin group

• Relapse and reinfection rate in patients with microbiological clearance were the same • Drug acquisition cost significantly lower in FT group

Author’s Conclusion

• Fosfomycin may be a suitable, effective and cheaper alternative in treatment of ESBL-producing E. coli-related complicated UTI in patients without fever or leukocytosis

• Speculate that increasing fosfomycin to every other day for 6 doses or administering fosfomycin IV may increase the response rate

Strengths • Active comparator • Conservative identification of efficacy

Limitations • Small sample size (difference could be due to random chance)

Table 22: Baseline Characteristics

Table 23: Risk Factors for Complicated UTI

Table 24: Comparison of Efficacy

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• Single center • Only evaluated E. coli • Not randomized • Other than catheterization does not report complicating factors by group • Different duration of therapy between the two groups

Take Home Points

• May consider treating complicated UTI with ESBL-producing E coli in patients with no systemic signs of infection

• Fosfomycin may potentially be a carbapenem-sparing, inexpensive and effective therapy for stable patients with mild complicated UTI

• If using fosfomycin to treat complicated UTI, would consider using a longer dosing regimen • The lower rates of response in this group of patients in the fosfomycin group could be due to the

higher rates of catheterization or higher rates of multiple complicating factors

C. Economic advantage of using fosfomycin for UTI34 Regimen AWP ($) Unit cost at VA ($) Duration

(per Senol et al.) Treatment

cost at VA ($) Treatment cost per

AWP ($) Fosfomycin 80 41.16 3 doses 123.48 240 Ertapenem 120 37.70 14 doses 527.80 1680

Ertapenem Treatment with Home Health at VA (7 day course) 1071.70

D. Possible emergency of resistance35 1. In vitro studies indicated resistance mutations to fosfomycin are more likely to develop in P. aeruginosa

and K. pneumoniae isolates than in E. coli isolates 2. No reports of resistance emergence in E. coli isolates during or after therapy 3. Overall changes in resistance are low in E. coli over 5 years

IV. Conclusions and Recommendations A. Conclusion

1. Fosfomycin may be the only oral option available in patients with UTI due to MDR pathogens based on the increased resistance rates to first-line agents

2. In vitro data indicate fosfomycin has > 90% susceptibility in MDR E. coli and there is limited resistance development on therapy and limited resistance emergence over time

3. Limited in vivo data suggest that fosfomycin may be a carbapenem-sparing, non-inferior therapy for MDR E. coli UTIs

B. Recommendations

1. Complicated cystitis when no systemic symptoms or signs of infection are present a. Avoid empiric use of fosfomycin in complicated UTI b. Culture-directed use of fosfomycin in complicated UTI due to E. coli c. Susceptibility-directed use of fosfomycin in complicated UTI due to Klebsiella spp. d. Susceptibility-directed use of fosfomycin in complicated UTI due to Enterococcus spp. e. Avoid use of fosfomycin in UTI due to Pseudomonas spp. and Acinetobacter spp.

2. May consider longer duration of therapy when treating complicated UTI with fosfomycin

C. Future Directions 1. How would fosfomycin compare to carbapenems in a more robust study? 2. What is the optimal dosing of fosfomycin in complicated UTI? 3. Which risk factors for complicated UTI are associated with higher rates of efficacy with fosfomycin? 4. Will fosfomycin resistance develop quickly with increased use?

Table 25: Costs of Different Treatment Regimens

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Appendix A: National Healthcare Safety Network (NHSN) Criteria 201336, 37 CAUTI (1, 2 and 3) 1. Patient had an indwelling urinary catheter that had been in place for > 2 days on the date of event 2. Patient has at least one of the following signs or symptoms:

• fever (>38.0°C) • suprapubic tendernessa • costovertebral angle pain or tendernessa • urinary urgencyb • urinary frequencyb • dysuriab

3. Patient has a urine culture with at most two species of organisms identified, at least one of which is a bacterium of ≥

105 cfu/ml SUTI (1, 2 and 3) 1. Patient does not have a urinary catheter in place or patient has a catheter in place but it has been in place < 2 days

2. Patient has at least one of the following signs or symptoms

• fever (>38°C) in a patient that is ≤ 65 years of age • suprapubic tendernessa • costovertebral angle pain or tendernessa • urinary frequencyb • urinary urgencyb • dysuriab

3. Patient has a urine culture where ≤ two species of organisms were identified, at least one of which is a bacterium of

≥ 105 cfu/ml a No other recognized cause b These symptoms cannot be used when catheter is in place Change from 2008 to 2013 criteria “No other recognized cause” label removed from fever