Prostatitis, Escherichia Coli Infection
Conditions
Keywords
Multi-drug resistance, Sequential oral treatment, Fosfomycin, Acute bacterial prostatitis, Escherichia coli
Brief summary
FOS-PROST was a prospective, non-randomized, controlled phase IV clinical trial designed to evaluate the clinical and microbiological efficacy of oral fosfomycin trometamol as sequential antibiotic therapy in patients with acute bacterial prostatitis caused by multidrug-resistant \*Escherichia coli\*. According to the study protocol, patients with multidrug-resistant \*E. coli\* were assigned to receive oral fosfomycin trometamol, whereas patients with non-multidrug-resistant \*E. coli\* were assigned to receive conventional oral antibiotic treatment with ciprofloxacin or trimethoprim-sulfamethoxazole, according to antimicrobial susceptibility testing. All patients received 1 to 5 days of appropriate intravenous antibiotic therapy before switching to oral treatment. Fosfomycin trometamol was administered at a standard dose of 3 g once daily. The planned total duration of antibiotic treatment was 21 days in both groups, including intravenous and oral therapy. During study conduct, some patients with non-multidrug-resistant \*E. coli\* also received fosfomycin. All patients with multidrug-resistant \*E. coli\* received fosfomycin. Clinical and microbiological outcomes were compared between treatment groups. Secondary objectives included evaluating carbapenem consumption, hospital length of stay, safety, recurrence, and fosfomycin pharmacokinetics.
Detailed description
Acute bacterial prostatitis caused by multidrug-resistant \*Escherichia coli\* represents a therapeutic challenge because resistance to commonly used oral antibiotics limits treatment options and may increase the need for prolonged intravenous antibiotic therapy. FOS-PROST was a multicenter, prospective, non-randomized, controlled phase IV clinical trial investigating oral fosfomycin trometamol as sequential antibiotic treatment for acute bacterial prostatitis caused by multidrug-resistant \*E. coli\*. Eligible adult male patients with microbiologically confirmed acute bacterial prostatitis caused by \*E. coli\* were enrolled. All participants received 1 to 5 days of appropriate intravenous antibiotic therapy before switching to oral treatment, once clinical stability and the conditions for oral sequential therapy had been achieved. According to the study protocol, patients with multidrug-resistant \*E. coli\* were assigned to receive oral fosfomycin trometamol at a standard dose of 3 g every 24 hours. Patients with non-multidrug-resistant \*E. coli\* were assigned to receive conventional oral antibiotic therapy with ciprofloxacin or trimethoprim-sulfamethoxazole, according to antimicrobial susceptibility testing. The planned total duration of antibiotic treatment was 21 days in both groups, including intravenous and oral therapy. During study conduct, some patients with non-multidrug-resistant \*E. coli\* received oral fosfomycin rather than conventional oral antibiotic therapy. All patients with multidrug-resistant \*E. coli\* received fosfomycin. The study evaluated clinical cure and microbiological cure as separate efficacy outcomes. Secondary outcomes included recurrence, adverse events, carbapenem consumption, hospital length of stay, and fosfomycin pharmacokinetics. The statistical analysis included a comparison according to the treatment actually received (as-treated analysis) and a per-protocol analysis excluding patients who did not meet the protocol-defined treatment allocation criteria.
Interventions
Oral fosfomycin trometamol, 3 g every 24 hours, administered as sequential antibiotic therapy after 1 to 5 days of appropriate intravenous antibiotic treatment, once clinical stability and oral tolerance were achieved. The planned total duration of antibiotic treatment, including intravenous and oral therapy, was 21 days. Dose adjustments for renal impairment were specified in the protocol.
DRUGcontrol group
Oral ciprofloxacin, 500 mg every 12 hours, administered as sequential antibiotic therapy according to antimicrobial susceptibility testing, following 1 to 5 days of appropriate intravenous antibiotic treatment. The planned total duration of antibiotic therapy was 21 days.
Sponsors
Hospital Mutua de Terrassa
Parc Taulí Hospital Universitari
Consorci Sanitari de Terrassa
Hospital del Mar
Clinica Universidad de Navarra, Universidad de Navarra
Hospital Álvaro Cunqueiro
Hospital de Sant Joan Despí Moisès Broggi
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective, non-randomized, open-label, parallel-group phase IV clinical trial. According to the protocol, patients with acute bacterial prostatitis caused by multidrug-resistant Escherichia coli were assigned to receive sequential oral fosfomycin trometamol, whereas patients with non-multidrug-resistant E. coli constituted the prospective comparator group and were assigned to receive conventional oral antibiotic treatment with ciprofloxacin or trimethoprim-sulfamethoxazole. Treatment allocation was based on the antimicrobial susceptibility profile rather than randomization.
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\*\*Inclusion Criteria:\*\* Male patients aged 18 years or older with febrile acute bacterial prostatitis (temperature \>37.5°C) caused by Escherichia coli. Diagnosis required a prostate-specific antigen (PSA) level \>4 μg/L, at least one microbiological criterion, and at least two clinical criteria as specified below. \*\*Microbiological Criteria (at least one required):\*\* 1. Urine culture yielding \>100,000 CFU/mL of multidrug-resistant (MDR) Escherichia coli for the experimental group or non-MDR E. coli for the control group, with a fosfomycin minimum inhibitory concentration (MIC) ≤32 mg/L in both groups. 2. Positive blood culture for MDR E. coli in the experimental group or non-MDR E. coli in the control group, with a fosfomycin MIC ≤32 mg/L in both groups, accompanied by clinical signs of sepsis without another evident or probable source of bacteremia and pyuria (≥10 leukocytes/mm³ or positive leukocyte esterase on urine dipstick). \*\*Clinical criteria (at least two required):\*\* 1. Lower urinary tract symptoms: * Irritative symptoms: urinary urgency, increased urinary frequency, dysuria, or tenesmus. * Obstructive symptoms: difficulty initiating urination, decreased urinary stream, postvoid residual urine, or acute urinary retention. 2. Perineal pain, spontaneous or associated with urination: * Pain involving the suprapubic, perineal, lumbosacral, scrotal, penile, or inner thigh regions. * Enlarged, warm, or tender prostate on digital rectal examination. 3. History of prostatic disease (prostate cancer or benign prostatic hyperplasia) associated with: * Recent urinary tract instrumentation. * Recent transrectal prostate biopsy (\<7 days). * Altered level of consciousness in patients older than 70 years without another apparent cause. \*\*
Exclusion criteria
\*\* 1. Known allergy or intolerance to fosfomycin. 2. Polymicrobial bacteremia or polymicrobial urine culture. 3. Clinical evidence of acute pyelonephritis, including costovertebral angle tenderness, urinary tract obstruction, or renal abscess. 4. Anatomical abnormalities of the urinary tract. 5. Catheter-associated urinary tract infection. 6. Undrained prostatic abscess. 7. Another concomitant infection. 8. Failure to achieve clinical stability after five days of parenteral antibiotic treatment. 9. Septic shock at the time of treatment allocation. 10. Polycystic kidney disease. 11. History of chronic prostatitis. 12. Recurrent acute bacterial prostatitis, defined as two or more episodes during the preceding year or one episode during the preceding six months. 13. Immunosuppression, including kidney transplantation, liver cirrhosis, renal replacement therapy, chronic corticosteroid treatment, active chemotherapy, or anti-TNF therapy. 14. Terminal illness, estimated life expectancy of less than 90 days, or exclusive palliative care. 15. Participation in another clinical trial involving active treatment. 16. Fosfomycin MIC exceeding the susceptibility threshold specified in the study inclusion criteria. 17. Refusal to provide informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Cure | Day 21 ± 3 days from treatment initiation (end of treatment) | Clinical cure was defined as the resolution of all symptoms present at baseline without the need for additional antibiotic treatment. Clinical cure required the absence of fever (axillary temperature greater than 38°C), urinary symptoms (dysuria, urinary frequency, urgency, or suprapubic pain), and altered level of consciousness if present at baseline. |
| Percentage of Participants With Microbiological Cure | Day 21 ± 3 days from treatment initiation (end of treatment). | Microbiological cure was defined as a negative urine culture at the end of antibiotic treatment. Only participants with an available urine culture at the end-of-treatment assessment were included in the analysis of this outcome. Participants without an available urine culture were excluded from the microbiological cure analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Carbapenem Defined Daily Doses (DDDs) Avoided per Patient | During the 21-day antibiotic treatment period. | The potential carbapenem-sparing effect of sequential oral fosfomycin trometamol was estimated in patients with acute bacterial prostatitis caused by multidrug-resistant Escherichia coli. Assuming that these patients would otherwise have received intravenous ertapenem until completion of the planned 21-day antibiotic course, the number of potentially avoided ertapenem Defined Daily Doses (DDDs) was calculated based on the remaining treatment duration after switching to oral fosfomycin. Results were expressed as estimated DDDs avoided per patient. |
| Hospital Length of Stay in Days | During the hospital admission for the acute bacterial prostatitis episode. | Hospital length of stay was assessed as the number of days of actual hospital admission during the acute bacterial prostatitis episode and compared between the fosfomycin and control group. In accordance with the study protocol, patients with hospital-acquired multidrug-resistant Escherichia coli infection were excluded from this analysis |
| Estimated Hospitalization Days Avoided per Patient | During the 21-day antibiotic treatment period | The potential reduction in hospital or hospital-at-home admission days associated with sequential oral fosfomycin trometamol was estimated among patients receiving oral fosfomycin. Assuming that these patients would otherwise have required continued parenteral antibiotic therapy during hospital or hospital-at-home admission, the number of potentially avoided admission days was estimated from the remaining days of the planned 21-day antibiotic treatment course after switching to oral fosfomycin. Results were expressed as estimated admission days avoided per patient. |
| Plasma Fosfomycin Concentration | At 1, 2, 4, 12, and 24 hours after the first oral fosfomycin dose; additional trough concentrations during hospitalization or at Visit 4, as applicable. | Plasma fosfomycin concentrations (mg/L) were planned to be measured using blood samples collected at predefined time points after oral fosfomycin trometamol administration in selected participants at the coordinating center. The planned pharmacokinetic assessment was not performed, and no plasma fosfomycin concentration data were collected. |
| Percentage of Participants Experiencing Adverse Events | From treatment initiation through Day 51 (± 7 days). | The incidence and severity of adverse events were assessed in patients receiving sequential oral fosfomycin trometamol or conventional oral antibiotic therapy. Adverse events were recorded during antibiotic treatment and subsequent follow-up through Day 51 (± 7 days) from treatment initiation. Results were expressed as the number and percentage of participants experiencing adverse events in each treatment group, with assessment of their severity. |
| Acute Bacterial Prostatitis-Related Mortality | From treatment initiation through Day 51 (± 7 days). | Mortality related to the acute bacterial prostatitis episode was assessed in both treatment groups. The outcome was measured as the number and percentage of participants who died from causes attributable to the acute bacterial prostatitis episode during the study observation period. |
| Incidence of Acute Bacterial Prostatitis Recurrence | From completion of antibiotic treatment through Day 51 (± 7 days) from treatment initiation. | The incidence of acute bacterial prostatitis relapse or reinfection was assessed prospectively during the protocol-defined follow-up period. Relapse was defined as recurrence of urinary tract infection symptoms with isolation of the same microorganism, whereas reinfection was defined as recurrence of symptoms with isolation of a different bacterial strain. Results were expressed as the number and percentage of participants experiencing relapse or reinfection in each treatment group. |
| Incidence of Emergent Fosfomycin Resistance | From treatment initiation through Day 51 (± 7 days). | The emergence of fosfomycin resistance was planned to be assessed through microbiological susceptibility testing during treatment and follow-up in participants receiving oral fosfomycin trometamol. This assessment was not performed, and no data on emergent fosfomycin resistance were collected. |
Countries
Spain
Outcome results
None listed