INTERNATIONAL EPIDEMIOLOGICAL STUDY ON

MICROBIOLOGY OF UNCOMPLICATED UTIs.

PROSPECTIVE MULTICENTER,

OBSERVATIONAL EPIDEMIOLOGICAL SURVEY

SURVEILLANCE STUDIESON THE

EPIDEMIOLOGY OF RESISTANCEBECOME INSTRUMENTAL

IN GUIDINGEMPIRIC THERAPY

OFUNCOMPLICATED UTIs

ARESC STUDY

September 2003 June 2006

ARESC STUDY END-POINTS

PRIMARY:

Prevalence and susceptibility of pathogens in uncomplicated lower, community acquired UTIs

SECONDARY:

Prevalence and susceptibility of pathogens in patients with recurrent UTIs and during pregnancy

Female patients aged between 18 and 65 years Pregnant women included

Symptoms of uncomplicated UTI

Positive culture defined as a sample with 104 cfu/ml in midstream urine

Recurrent uncomplicated UTI (defined as 3 episodes of UTI in the last year ) included

Informed consent

INCLUSION CRITERIA

ARESC STUDY

4264 patients enrolled

3018bacterial pathogens analyzed

AUSTRIA: 3

BRASIL: 6

FRANCE:10

GERMANY: 8

HUNGARY: 5

ITALY: 6

NETHERLANDS: 2

POLAND: 6

RUSSIA: 10

SPAIN: 9

SITES DISTRIBUTION

RUSSIA

BRASIL

SPAIN

GERMANY

ITALY

AUSTRIA

HUNGARY

FRANCE

THE NETHERLANDS

POLAND

10 COUNTRIES

65 CENTERS

Patient characteristics

50,80%

52,17%

33%

30,06%

16,20%

17,77%

0%

10%

20%

30%

40%

50%

60%

18-35y 36-55y 56-65y

Mean: 38.2 years Mean: 38,0 years

SPAIN

GLOBAL

Patient characteristics

94,80% 96,30%

5,20% 3,70%

0%

20%

40%

60%

80%

100%

Pregnant Not-pregnant

Mean: 38.2 years Mean: 38,0 years

SPAIN

GLOBAL

2,90% 4,20%

22,30% 24,00% 24,80% 25,70%

55,10%

50,10%

56,70%57,40%

77,10%75,00%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Diabetes Constipation Menopause Contraceptivemethod

Children Sexualintercourse

Patient Characteristics

SPAINGLOBAL

Patient Symptoms

67,25%

75,35%

91,53% 92,72%90,24%

88,63%

94,53%91,83%

16,52%

28,76%

15,20% 17,88%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0-3 d onset Dysuria Urgency Frequency Hematuria Fever

SPAINGLOBAL

TYPES OF INFECTION

90%

10%

Recurrent UTI Non-recurrent UTI

86%

14%

SPAIN

GLOBAL

TYPES OF INFECTION

4%

96%

Single pathogen Mixed infections

1%

99%

SPAIN

GLOBAL

URINEANALYSIS

89%

11%

CFU = 10E4 CFU >10E4

99%

1%

SPAIN

GLOBAL

URINEANALYSIS

6%

94%

Midstream urine S. Cateter urine

0%

100%

SPAIN

GLOBAL

PATHOGENS TESTED

Country Strain N°

Spain 650

Brasil 506

France 488

Russia 416

Italy 329

Germany 317

Poland 119

Austria 91

Hungary 66

The Netherlands 36

Total 3018

AETIOLOGYof uncomplicated UTIs

E.coli 76.7%

3018 uropathogens

Other ENT: Klebsiella spp., Enterobacter spp., Citrobacter spp., H.alvei, M.morganii, Pantoea spp., Serratia spp., Salmonella spp.Other not-ENT: P.aeruginosa, B.cepacia

Other G+: Enterococcus spp., S.aureus, Staphylococcus coagulase -, Streptococcus spp.

E.coli 515 (79.23)%)K.pneumoniae 15 (2.31%)S.saprophyticus 29 (4.46%)P. mirabilis 28 (4.31%)Other ENT 12 (1.85%)Others 4 (0.62)Other G+ 47 (7.23%)

AETIOLOGYof uncomplicated UTIs

(Spain

E.coli 79.2%

650 uropathogens

Other ENT: Klebsiella spp., Enterobacter spp., Citrobacter spp., H.alvei, M.morganii, Pantoea spp., Serratia spp., Salmonella spp.Other not-ENT: P.aeruginosa, B.cepacia

Other G+: Enterococcus spp., S.aureus, Staphylococcus coagulase -, Streptococcus spp.

0

10

20

30

40

50

60

70

80

%

18-35 y (2158) 36-55 y (1402) 56-65 y (685)

E.coli S.saprophyticus P.mirabilis K.pneumoniae Other ENT * Others °

AETIOLOGYage groups

*Enterobacter spp., Citrobacter spp., Klebsiella spp., H.alvei, M.morganii, Pantoea spp., Serratia spp., Salmonella spp.°P.aeruginosa, B.cepacia, Enterococcus spp., S.aureus, Staphylococcus coagulase -, Streptococcus spp.

•

Country % N°

France 83.8 409

The Netherlands 80.6 29

Spain 79.2 515

Hungary 78.8 52

Germany 76.7 243

Poland 75.6 90

Brasil 73.9 374

Italy 72.6 239

Russia 72.6 302

Austria 68.1 62

Total 76.7 2315

E.coli INCIDENCE

0

10

20

30

40

50

60

70

80

90

RecurrentITU

Diabetes Pregnancy BactCharge >

10E4

Nitrites Hematuria

% incidence

NO

YES

Influence of patient’ characteristics on E. Coli incidence

On the other parameters as: Menopause, Sexual intercouse, Constipation, Kind of sample or Fever: No significant differences were observed

Mean76,7

Antibiotic

%

S I + R

Fosfomycin 98.2 1.8

Mecillinam 95.9 4.1

Nitrofurantoin 95.2 4.8

Ciprofloxacin 91.3 8.7

Amoxi/clav. 81.9 18.2

Nalidixic acid 81.4 18.6

Cefuroxime axetil 81.0 19.0

Co-trimoxazole 70.6 29.4

Ampicillin 45.1 54.9

2315 E.coli GLOBAL SUSCEPTIBILITY PATTERNS

AntibioticMIC (mg/L) %

Range MIC50 MIC90 S I R

Fosfomycin <1-512 2 8 97.3 1.5 1.2

Mecillinam <0.12->128 0.5 4 94.2 1.7 4.1

Nitrofurantoin <0.5-256 16 32 94.2 3.7 2.1

Amoxi/clav. 0.25/0.12- 128/64 8/4 16/8 77.7 18.6 3.7

Cefuroxime axetil 0.25->128 4 8 75.3 22.9 1.8

Ciprofloxacin <=0.015->16 <0.015 8 88.1 0.2 11.7

Nalidixic acid <0.12->128 4 >128 73.6 / 26.4

Co-trimoxazole <0.015/0.30->16/304 0.5/9.5 >16/304 66.2 / 33.8

Ampicillin 1->128 >128 >128 35.3 4.7 60.0

E.coli SUSCEPTIBILITY PATTERNS

(650) Spain(650) Spain

Antibiotic%

S I + R

Ciprofloxacin 94.4 5.6

Amoxi/clav. 90.7 9.3

Fosfomycin* 87.9 12.1

Nalidixic acid 82.2 17.7

Cefuroxime axetil 78.5 21.5

Co-trimoxazole 76.6 23.4

Nitrofurantoin 17.8 82.2

Ampicillin 0 100

107 K.pneumoniaeGLOBAL SUSCEPTIBILITY PATTERNS

* : presumptive breakpoint (S< 64 mg/L)

Antibiotic%

S I + R

Amoxi/clav. 94.2 5.8

Cefuroxime axetil 93.3 6.7

Ciprofloxacin 90.4 9.6

Fosfomycin * 86.4 13.6

Nalidixic acid 78.8 21.2

Ampicillin 67.3 32.7

Co-trimoxazole 62.5 37.5

Nitrofurantoin 0 100

104 P.mirabilisGLOBAL SUSCEPTIBILITY PATTERNS

* : presumptive breakpoint (S< 64 mg/L)

ARESC STUDY: CONCLUSIONS

• E.coli has been confirmed to represent the most common agent of uncomplicated UTIs

• AMPICILLIN and SXT most affected by resistance

• Agents used specifically in UTIs- FOSFOMYCIN- MECILLINAM- NITROFURANTOINexhibited low levels of R in all participating countries both in recurrent and not recurrent UTIs

• For FQ and other β-lactams local epidemiological data are mandatory for a correct empiric therapy (R rates >10-20%)

First line therapy of uncomplicated UTI with fosfomycin: CM advantages

• Appropriate spectrum

• Minimal resistance in the primary pathogen

• Resistant clones crippled

• Overcomes resistance to unrelated drugs

INITIAL EMPIRIC THERAPY:

FOSFOMYCIN TROMETAMOL: 1dNITROFURANTOIN: 5-7d

PIVMECILLINAM: 7d

Only after consideration of LOCAL Resistance rates:

Co-trimoxazole (3 d)Trimethoprim (5-7 d)

Fluoroquinolones (3 d)Naber et al., 2006

EUROPEAN ASSOCIATION OF UROLOGY2006 GUIDELINES

FOR TREATMENT OF UNCOMPLICATED UTIs

Objetivos de la guía

Pacientes diana: criterios de inclusión

• El paciente diana es toda mujer afecta de cistitis no complicada, definida como

aquella infección urinaria que ocurre en personas que tienen un tracto urinario

normal, sin alteraciones funcionales o anatómicas, sin historia reciente de

instrumentación (sondaje, uretrocistoscopia) y cuyos síntomas se presentan

confinados en la vejiga.

• Las pacientes diana presentan una edad comprendida entre los 16 años y sin

límite de edad máxima. Esta decisión está basada en la edad de inicio de las

relaciones sexuales entre los jóvenes españoles[i]. No obstante, también se

incluirán las pacientes de 14 y 15 años que sean sexualmente activas.

[i] Informe juventud en España 2004, capítulo 6, página 120.

• Escherichia coli sigue siendo el principal uropatógeno (70-80%) y pone de manifiesto un aumento paulatino y sostenido de su resistencia a algunos de los antibióticos de mayor uso terapéutico en la comunidad.

• Entre los criterios de elección de un determinado antibiótico para el tratamiento empírico de la infección urinaria no complicada es importante considerar dos aspectos:

– Que presente una baja prevalencia de resistencias bacterianas (< 20%)

– Que sea de fácil cumplimiento (pauta corta que asegure el mantenimiento de los niveles de asntibiótico durante 3 días)

• Estas recomendaciones se han priorizado en función de los siguientes criterios:

– Sensibilidades de los gérmenes más frecuentemente implicados

– Eficacia

– Coste y duración del tratamiento

RECOMENDACIONES FINALES

RECOMENDACIONES FINALES

Tratamiento de 1ª elección:

Fosfomicina trometamol en una única monodosis de 3 g

Tratamiento de 2ª elección:

Sulfametoxazol-Trimetoprim, 800/160 mg/12 horas durante 3 días (en aquellas áreas con resistencias a E. Coli inferior al 20%)

Norfloxacino, 400 mg/12 horas durante 3 días

Ciprofloxacino, 250 mg/12 horas durante 3 días

Amoxicilina-ácido clavulánico, 500/125 mg/8 horas durante 5 días

Cefixima, 400 mg/24 horas durante 3 días