# Presentation: 059483

## Acute or Chronic Bacterial Prostatitis

- Regina Alivisatos, MD
- DSPIDPs

- July 1998

## Current Classification System (Drach et al) 

- Acute Bacterial Prostatitis
- Chronic Bacterial Prostatitis
- Non-bacterial Prostatitis
- Prostadynia

- July 1998

## NIH Consensus Conference on Prostatitis (1995)

_**Category I**_: Acute Bacterial Prostatitis = Acute infection of the prostate gland
_**Category II**_: Chronic Bacterial Prostatitis = Recurrent infection of the prostate.

- July 1998

## NIH Consensus Conference on Prostatitis cont.

_**Category III**_: Chronic Abacterial Prostatitis/CPPS: No demonstrable infection
- _Category IIIA_: Inflammatory CPPS = WBCs in       semen/EPS/VB3
- _Category IIIB_: Noninflammatory CPPS = No WBCs in semen/EPS/VB3
_**Category IV**_: Asymptomatic Inflammatory Prostatitis

- July 1998

## Quinolone Antimicrobials with a prostatitis indication

**Ofloxacin** (1990): “Bacterial prostatitis caused by *Escherichia coli.”*
**Norfloxacin** (1992): “Prostatitis caused by *Escherichia coli.”*
**Ciprofloxacin** (1996): “Chronic bacterial prostatitis caused by *Escherichia coli* and *Proteus mirabilis*.
**Trovafloxacin** (1997): “Chronic bacterial prostatitis caused by *Escherichia coli,* *Enterococcus faecalis* and *Staphylococcus epidermidis.”*

- July 1998

## Disease DefinitionsKunin Calvin M.: Urinary Tract Infections, Detection, Prevention, and Management.  Fifth edition, 1997.

- “**Acute bacterial prostatitis**:  a suppurative process characterized by fever, chills, leucocytosis, and acute perineal and low back pain.  In more severe cases there may be bacteremia, shock, and DIC”.
- Blood cultures are often positive with the same microorganism found in the urine.
*Escherichia coli* and other uropathogens are considered to be the etiologic agents.”

- July 1998

## Disease DefinitionsKunin Calvin M.: Urinary Tract Infections, Detection, Prevention, and Management.  Fifth edition, 1997.

-  “**Chronic bacterial prostatitis**: “asymptomatic or characterized by a sensation of perineal fullness, low back pain, dysuria, and pyuria.  Fever is less common.”
- Same microorganism present with each recurrent episode.
- Difficult to eradicate because of the presence of prostatic calculi.
- The microorganisms are the same uropathogens as found in UTIs.
- “Coagulase-negative staphylococci, alpha-hemolytic streptococci*,* and diptheroids are part of the normal flora of the male urethra and only rarely cause infections.”

- July 1998

## Generally, submissions for this indication provide for subjects with the chronic form of this disease as opposed to the acute.  
Difficulty in obtaining appropriate bacteriologic specimens in patients suffering from true acute disease (possibility of bacteremia while performing prostatic massage).

- Difficulty in obtaining appropriate bacteriologic specimens in patients suffering from true acute disease (possibility of bacteremia while performing prostatic massage).

**Evaluability Issues**

- July 1998

## Strongly recommended that for labeling
purposes,  documentation be
provided with regards to:
 The duration of the present episode
 The duration of the disease 

- purposes,  documentation be
- provided with regards to:
-  The duration of the present episode
-  The duration of the disease

**Evaluability Issues cont..**

- July 1998

## Inclusion Criteria 

- An evaluable patient should present within
-  - 5 to 0 days of starting the study drug with:
- A tender, tense prostate on rectal exam (acute)
-                               OR
- A soft, tender prostate without nodules (chronic)
-                                          _**and**_

- July 1998

## One or more of the symptoms from the following:
Disturbances of urination (frequency, urgency, dysuria)
Lower urinary tract obstruction (hesitancy, decreased stream, urinary retention) 
Perineal or low back pain 
Fevers or chills. 

- Disturbances of urination (frequency, urgency, dysuria)
- Lower urinary tract obstruction (hesitancy, decreased stream, urinary retention)
- Perineal or low back pain
- Fevers or chills.

**Inclusion Criteria cont.**

- July 1998

## Bacteriologic Assessment Sequential urine cultures (Mears and Stamey)

**Voided bladder 1 (VB****1****)** : Initial 5-10 mL of urine specimen.
**Voided bladder 2 (VB****2****)** : Clean-catch midstream urine specimen.
**Expressed prostatic secretions (EPS)** : Secretions expressed from prostate by digital massage after midstream urine specimen.
**Voided bladder 3 (VB****3****)** : First 5-10 mL of urine stream immediately after prostatic massage.

- July 1998

## The diagnosis of acute or chronic bacterial
prostatitis is confirmed by one of the
following criteria:
The colony count of a pathogen in VB3 exceeds that in VB1 or VB2 by 10 fold
The colony count of a pathogen in EPS exceeds that in VB1 or VB2 by 10 fold.

- prostatitis is confirmed by one of the
- following criteria:
- The colony count of a pathogen in VB3 _exceeds _that in VB1 or VB2 by _10 fold_
- The colony count of a pathogen in EPS _exceeds _that in VB1 or VB2 by _10 fold._

**Bacteriologic Assessment cont.**

- July 1998

##  In the face of a true “acute” prostatitis
Not clinically indicated to perform a prostatic massage.  
Division will accept patients with a clinical picture consistent with acute disease including a tender prostate as determined by rectal exam and with a VB2 specimen with  105 CFU/mL of an accepted pathogen.  

- Not clinically indicated to perform a prostatic massage.
- Division will accept patients with a clinical picture consistent with acute disease including a tender prostate as determined by rectal exam and with a VB2 specimen with  105 CFU/mL of an accepted pathogen.

**Bacteriologic Assessment cont.**

- July 1998

## Exclusion Criteria

- Known prostatic cancer.
- Presence of any other infection at enrollment that may require treatment with an antibiotic other than the study drug.
- Treatment with any systemic antibiotic for 24 hours or longer within seven days prior to entry into the study, unless there is documented evidence of bacteriological and clinical failure.

- July 1998

##  Those patients who received another antimicrobial for a disease unrelated to the prostate and which might have had some effect on the disease under study during therapy or the FULL study period.  This does not apply to patients who receive an additional antimicrobial for the treatment of prostatitis who would be considered evaluable failures.

 Those patients who were lost to follow-up  or who do not  have documentation of microbiologic outcome.This does not apply to patients who were previously-documented failures.

-  Those patients who were lost to follow-up  or who do not  have documentation of microbiologic outcome.This does not apply to patients who were previously-documented failures.

**Unevaluable**

- July 1998

## Baseline Visit(pre-therapy, screening and start of therapy visit)

- -5 to 0 days prior to the start of therapy.
- May coincide with randomization and start of therapy (acutely ill population) or
- May be split into 2 visits, an initial pretherapy/screening visit followed by a visit up to 5 days later to start therapy (chronic).

- July 1998

## On-therapy Visit

- 3 – 10 days after the start of therapy.
- visit may be substituted by telephone contact with the patient. Not necessary for evaluability.
- The evaluation should include a clinical assessment of the symptoms of bacterial prostatitis (efficacy assessment).

- July 1998

## FDA TOC Visit 5 – 9 days post-End Of Therapy (EOT)

- Should include an efficacy evaluation (rectal prostate exam)
- Global clinical assessment
- Quantitative bacteriological culture
- If expressed prostatic secretion (EPS) cannot be obtained after prostatic massage, bacteriological efficacy may be based on urine cultures from VB1, VB2, _and_ VB3

- July 1998

## End Of Study (EOS) Visit 4 – 6 weeks after the EOT 

- Utilized solely to assess for recurrence in those subjects cured at the previous visit.
- Efficacy evaluation should include a digital examination of the prostate.
- Global clinical assessment
- Quantitative bacteriological cultures

- July 1998

## Outcome Assessment

**Symptom Assessment Instrument**
- No validated Scoring system
- Quantitation important for outcome assessment

- July 1998

## Outcome Assessment cont.

- Prostatitis evaluability should include both a clinical and a microbiological assessment at the 5 - 9 day post-therapy visit (TOC).

- July 1998

## Outcome Assessment Clinical (TOC = 5 -9 days post-therapy)

**Cure:** the complete or significant resolution of all pretherapy signs and symptoms.
**Failure:** no response to therapy or worsening of most/all pre-therapy signs and symptoms.

- July 1998

## The category of “improvement” has been omitted in order to provide for a dichotomous "cure/fail" analysis.

Any subject considered a failure at a previous visit should be carried forward.

- Any subject considered a failure at a previous visit should be carried forward.

**Outcome Assessment ****Clinical**

- July 1998

## Eradication: A sequential culture obtained within the 5 - 9 days post-therapy window, that reveals that the pathogen isolated at entry has been eradicated from VB3 or EPS.
Persistence: A sequential culture obtained on or before the 5 - 9 days after the completion of therapy visit that reveals continued growth of the original pathogen (always carried forward as a failure) in the EPS or VB3 specimen.

**Persistence:** A sequential culture obtained on or before the 5 - 9 days after the completion of therapy visit that reveals continued growth of the original pathogen (always carried forward as a failure) in the EPS or VB3 specimen.

**Outcome Assessment**** ****Microbiological ****(TOC = 5 -9 days post-therapy)**

- July 1998

## Outcome Assessment  Microbiological (TOC = 5 -9 days post-therapy)

**Superinfection:** the isolation of a pathogen, other than the baseline pathogen in any on-therapy specimen, associated with worsening or emergence of clinical evidence of infection.

- July 1998

## Outcome Assessment 4-6 weeks post-therapy

- To be considered evaluable for this visit, should have been considered a cure at the 5–9 day post-therapy or TOC visit.
- All previous failures should be carried forward as failures.

- July 1998

## Outcome Assessment Clinical (4 - 6 weeks post-therapy)

**Sustained Cure**: all or most pre-therapy signs and symptoms remain resolved at the 4 - 6 week post-therapy visit in subjects classified as cures at the 5- 9 days post-therapy visit.
**Failure:** all patients who were failures at 5 -9 days post-therapy carried forward.
**Relapse:** signs and symptoms absent at the 5 - 9 day post-therapy visit that re-appear at the 4 - 6 week post-therapy visit.

- July 1998

## Microbiologic Assessment (4-6 weeks post-therapy)

**  ****Sustained Eradication**: a sequential culture obtained within the 4 - 6 week post-therapy window that reveals that the pathogen found at entry remains eradicated in the VB3 or EPS specimens.
**  ****Persistence:** Same definition as persistence above (a failure carried forward).
**  ****Recurrence:** the isolation of the original pathogen at any time in the EPS or VB3 specimens after the documented eradication of this organism at the 5 - 9 day post-therapy or TOC visit.

- July 1998

## Proposal

- The separation of acute versus chronic disease in order to provide for accurate labeling of the population under study.

- July 1998