Antibiotics
Most urologists will treat prostatitis empirically with a course of antibiotics prior to receiving the results of any bacteriologic studies that are performed. Furthermore, most would continue the antibiotic for a full course (2 to 12 weeks), irrespective of the culture results. The only change, typically, would be considered if the antibiogram indicated that a particular organism was resistant to the antibiotic employed. The time course for treatment is highly variable. Most authors and research indicate that a period of 30 days is adequate but literature exists to support as long as 3 to 6 months of therapy. A number of antibiotics have been touted as the most appropriate for the treatment of classic chronic bacterial prostatitis or category II; these drugs should be used in category IIIA as well. Carbenicillin indanyl sodium (Geocillin-Roche) was probably the first antibiotic to have a specific indication for the treatment of prostatitis. It has an excellent spectrum of activity but it is cumbersome for patients as it is dosed four times a day. The tetracyclines as a group have an appropriately broad spectrum and also have the ability to penetrate the prostate well. More specifically, the derivatives doxycycline and minocycline have been shown to be efficacious and also have the added benefit of covering the more fastidious organisms such as Mycoplasma, Ureaplasma, and Chlamydia. It is not clear as to whether these organisms have a role in the etiology of category IIIA prostatitis as ample opinion exists for either side of the argument. They are, however, pathogenic for the urinary tract and may cause infections that are confused with category III prostatitis. The disadvantage with this class is that they are bacteriostatic and therefore rely, at least in part, on host defenses for bacterial clearance. Since the advent of the fluoroquinolones, the treatment of prostatitis of a known bacterial etiology has been simplified. These drugs freely penetrate into the prostate and may be found in the glandular tissue as well as the prostatic secretions. Their dissociation constant (pKa) and lipid solubility facilitates this bioavailability but may also contribute to the neurologic side effects. This class of antibiotic is becoming the medication used most commonly either in the period after the initial physician visit but prior to receipt of the culture results or as empiric therapy. If the culture is negative, most clinicians still continue to treat for their prescribed time interval. Perhaps the most commonly employed agent worldwide for the treatment of “chronic” prostatitis is the sulfamethoxazole-trimethoprim combination.
TABLE. Common Symptoms in Prostatitis and Interstitial Cystitis
| 1. Voiding dysfunction |
| • Frequency |
| • Urgency |
| • Dysuria |
| • Pain |
| 2. Pelvic pain |
| • Ill-defined |
| • Difficult to locate |
| • Often associated with bladder filling |
| 3. Dyspareunia |
| 4. Associated inflammatory findings |
| 5. Paucity of characteristic physical examination findings |
| 6. Emotional overlay |
There are numerous references to support the theoretic reasons that these agents should be efficacious in these patients.” Most of the work in this area has used animal models, which may not be completely applicable to humans. On the other hand, many years of employing this combination in patients has lent credence to its efficacy.
There is some concern regarding delivery of certain antimicrobials to the prostate gland itself. Since bacteria may potentially be harbored in prostatic stones, prostatic ducts that are obstructed with inspissated secretions, or in their own protective glycoprotein matrix, it may be difficult to consolidate an agent in the prostate at a concentration sufficient to penetrate these adaptive defenses and eradicate the bacteria. There does not appear to be an appreciable difference between intravenous or oral routes of administration in the levels achieved, especially with the quinolones, which can dramatically affect the cost of therapy. Some authors have administered the antibiotics directly into the prostate. The secretory dysfunction of infected prostates has popularized this method. The results are variable for this method but there is potential for development of granulomatous prostatitis, using this route. The theoretic advantages appear to be superceded by the complexity of administration and the cost, not to mention potential adverse events.
The evidence for bacteria as an etiologic agent in category IIIA prostatitis is slowly accumulating, which, in turn, lends credence to empiric antibiotic therapy.” Since it was recognized that bacteria may construct a glycoprotein matrix in which they grow at a metabolically slowed rate while being relatively protected from the host defense mechanisms and antimicrobial agents,’ interest has increased in searching for bacteria that may be difficult to detect with conventional methodologies. This state may hamper the microbiologists’ efforts to isolate organisms using standard culture techniques. This holds true for the cell-wall-deficient/defective organisms like Mycoplasma, Chlamydia, and Ureaplasma, as well as L-forms. Where extended culture techniques are employed, unusual organisms have been isolated; the isolates are bacteria that so far had been assumed to be commensals and not actually involved in the infection itself. It remains to be seen whether these are the etiologic agents or not but this may explain why patients who have bacteriologically negative prostates may respond to antimicrobial therapy. The use of more sophisticated molecular biologic techniques has shown the presence of bacterial genetic material in many of these patients.’ Several problems exist with the use of molecular biologic techniques in the establishment of a bacterial diagnosis. First, they are so sensitive that very small amounts of contaminating bacteria may significantly affect the results. Second, the genes used occasionally make it daunting to identify the specific organism, and furthermore, information regarding sensitivity to antibiotics is little more than an empiric guess.
TABLE. Categorization of Prostatitis
| Category 1 | - Acute bacterial prostatitis |
| Category II | - Chronic bacterial prostatitis |
| Category IIIA | - Pelvic or prostatic pain, associated with inflammatory changes in prostatic secretions but absence of a microbial etiologic agent |
| Category 1MB | - Similarto IIIA but largely comprising pelvic floor spasm and absence of inflammatory changes in the prostatic secretions |
| Category IV | - Prostatic inflammation discovered by histopathologic examination of the prostate that is otherwise asymptomatic for other causes (biopsy, prostatectomy) |
The 16s ribosomal ribonucleic acid subunit has been found in a surprisingly large number of cases as has the m-Tet gene, which is a genetic sequence that is found in a modest number of uropathogens. In one study, bacteria were actually visualized in the prostate glands, using electron microscopy. The mere presence of bacterial genetic material (RNA or deoxyribonucleic acid [DNA]) or even organisms themselves does not prove unequivocally that the etiologic agents have been identified. It does, though, give a plausible explanation as to why a percentage of these patients respond to antibiotics and should suggest that further studies on a bacteriologic etiology for category III prostatitis should be conducted.
Clinical Trials
Few studies exist with respect to the use of antibiotics in category IIIA or chronic abacterial prostatitis. One of the problems is that this classification has only been adopted into use a short time ago, and its acceptance is not complete. Second, the degree to which the diagnosis is made differs from study to study. Last, patient accrual is difficult, owing to the fact that the great majority of patients, who come to the urologist with complaints similar to prostatitis, have usually already been treated with not one but several antibiotics, usually for a protracted time period. Most of these patients are actually seen by their primary care physician at the onset and are referred only after antibiotic failure.
In attempting therapy with empiric antibiotics, prior to knowing whether one is treating category II or category IIIA, it would seem prudent to use an agent that is best suited for penetration into the prostatic parenchyma. In general, the agent must be highly lipid soluble; it must have low protein binding, and have a high pKa, specifically on the order of 8.6.
TABLE. Antibiotics in the Treatment of Prostatitis
| Sulfamethoxazole-trimethoprim: most widely used |
| Carbenicillin indanyl sodium: first approved for prostatitis |
| Doxycycline and minocycline: broad spectrum, bacteriostatic |
| Fluoroquinolones: broad spectrum, and excellent prostatic penetration |
The spectrum of activity should be sufficiently broad while retaining a high degree of activity against gram-negative organisms as well as the known gram-positive uropathogens (group D streptococci, certain coagulase negative staphylococci, and others). No single antibiotic fits this description perfectly. As previously mentioned, the most widely used agent is the combination sulfamethoxazole-trimethoprim. It is inexpensive, has fair prostatic levels, and the spectrum of activity is excellent for the pathogens most commonly found. There have even been a few studies using sulfamethoxazole-trimethoprim in documented bacterial prostatitis with good results. Some questions, however, have arisen as to antibiotic levels in the human prostate.
The tetracycline group, specifically doxycycline and minocycline, has shown promise in the treatment of category II prostatitis. These drugs are more lipid soluble than tetracycline itself, and prostatic parenchymal levels are established. These drugs have been used extensively in the fertility literature as empiric treatment of leukocytospermia. This condition, in fact, possibly represents category IV prostatitis or perhaps category IIIA. It has been shown, in uncontrolled studies, to reduce leukocytes in both the semen and prostatic fluid. It does have the significant adverse effect of gonadotoxicity, which is, at least in part, reversible. Macrolide antibiotics such as azithromycin and clarithromycin are well concentrated in the prostate gland and are excreted slowly, enabling excellent levels of drug to be present for an extended period of time. The spectrum, however, does not include gram-negative organisms to a significant degree.
The 5-fluoroquinolones, such as ciprofloxacin, norfloxacin, and ofloxacin, are perhaps the agents of choice in category II prostatitis. This has led to clinicians using this drug as empiric therapy for category IIIA disease. These drugs reach abundant levels in the prostate and have a broad spectrum of activity. There are potential problems with theophylline toxicity, photosensitivity, and neurologic side effects as well as fertility concerns with ofloxacin. Lastly, as this group is more expensive than most other agents when therapy may take several weeks to complete, the cost may be substantial.
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