Therapeutic Dilemma of Bacterial Prostatitis Syndrome Jaber S. Orwa,* Mutwakil G. Ahmed,** Abstract: Objective: to investigate the aetiology and treatment of bacterial prostatitis syndrome in south Libya. Setting: El-Najah Polyclinic, Sebha, South Libya. Materials and Methods: This prospective study was conducted in El-Najah Polyclinic in the period from October 2003 to September 2006. The premassage and postmassage testing technique of prostatitis was employed to investigate patients with the clinical diagnosis of prostatitis syndrome. Collected specimens were cultured in Muller Hinton agar media for quantitative culture and sensitivity testing. Results: Out of a total of 250 patients with prostatitis syndrome, 88(35.2%) patients proved to have bacterial prostatitis. Escherichia coli (38.6%) was the commonest offending organism followed by Staphylococcus aureus (37.5%) and Pseudomonas auerginosa (11.3%). Gentamicin, Nitrofurantoin and Amoxycillin were the most effective agents against E. coli and Staphylococci. The vast majority of prostatic bacterial isolates were resistant to Erythromycin and Trimethoprim. Such pattern of resistance to these drugs described as the most effective agents for the treatment of bacterial prostatitis, indicates that treatment of bacterial prostatitis syndrome would pose a problem in this area. Trimethoprim-sulphamethoxazole and new quinolones were reported to have the best-confirmed cure rates in recent prospective bacterial protatitis studies and need to be investigated in a future study. Introduction: Inflammation of the prostate is one of the most common conditions in urologic practice, accounting for over 1 million office visits in the United States in 1991. Although many of these patients are treated with antibiotics, the cause of their prostatitis will probably not be identified with certainty. Many develop multiple recurrences of their symptoms and carry the clinical diagnosis of "chronic prostatitis" throughout their lives. 1 The cause of prostatitis is an area of replete with conflicting and confusing data. In the majority of cases, a causative agent is never found. In cases of proven bacterial protatitis, the organisms involved are those causing urinary tract infections in general, with E. coli being responsible for 80 per cent of cases. 2,3 The frequency of this organism is explained by the presence of receptors on human transitional epithelial cells which interact with P-fimbriae of E. coli. 4 Additional organisms identified as common causative agents of prostatitis are other gramnegative rods and enterococci. 2,3 The management of the various prostatitis syndromes remains a problem for the practicing clinical urologists in the 1990s. Although it was recognized in the 1930s that prostatitis could be caused by bacteria in the prostate gland, it was not until 1968 that Meares and Stamey described a standardized bacteriologic localization procedure for men with prostatitis syndromes. 5 This technique is based on sequential collection of a urethral specimen (initially voided urine UB1), bladder specimen (midstream urine UB2), and prostatic specimen (expressed prostatic secretion EPS), and urine voided immediately after massage (UB3). A clinically relevant classification based on this rigid bacteriologic diagnosis system had now become accepted by most researchers and practicing physicians 6 (Table 1). The original report of this technique included only five patients, was not properly controlled, and in fact has never validated. The majority of practicing urologists do not use this sequential culture technique. Informal polling of urologists at national and international meetings reveals that less than 5% routinely subject their patients with suspected prostatitis to this diagnostic technique. 7,8 *) Department of Microbiology, El-Najah Polyclinic, Sebha Libya. **) Department of Medicine, Faculty of Medicine, Sebha University, Sebha Libya. 64 Sebha Medical Journal, Vol. 6(1), 2007.
Subsequently, Nickel et al have recommended a simplified diagnostic technique employing only a preprostatic and postprostatic massage urine specimens (pre-m and post-m) in patients who do not have clinical urethiritis. 9 Leucocytosis seen in microscopy of the centrifuged sediment of those post-m specimen (> WBC/HPF or 1 Log greater than in pre-m) suggests prostatic inflammation. Cultures of the two specimens are interpreted similarly to the standard Meares-Stamey technique (Table 2). This proposed technique suffers from many of the limitations of the classic 3-glass test, but is simpler, cost-effective and generally accepted by urologists, casualty officers, and family physicians. This technique, involving microscopy and culture with addition of a simplified immunologic diagnostic step, has been tested and validated in a multicenter Canadian study. 9-11 Acute bacterial prostatitis usually has a dramatic presentation that is easily diagnosed by clinical symptoms and physical examination and is associated with acute urinary tract infection. The patient presents with malaise, fever, low back or perineal pain and myalgia for several days prior to onset of symptoms of urinary frequency, dysuria, urgency and varying degrees of bladder outlet obstruction. Palpation of the prostate, which must be done carefully, reveals a hard, tender irregular gland that is warm to touch. Prostatic fluid should not be obtained by massage because of the risk of bacteraemia. Because cystitis is associated with acute bacterial prostatitis, the responsible bacterial pathogen can be isolated from bladder urine. Table 1: The prostatitis syndrome Acute Bacterial prostatitis Chronic bacterial prostatitis Non-bacterial prostatitis Prostatodynia Acute inflammation of the prostate gland is characterized by leucocytosis in the prostatic fluid and positive bacterial cultures of the prostatic fluid (if obtained), bladder urine (usually) and blood occasionally. Chronic bacterial inflammation of the prostate gland is characterized by leucocytosis and positive bacterial cultures in the prostatic fluid but rarely in the bladder urine. Chronic inflammation of the prostate gland is characterized by leucocytosis of the prostatic fluid but no positive bladder or prostatic cultures of the "usual" bacterial pathogens. Prostate demonstrate no inflammation and cultures are sterile. Table 2: Premassage (pre-m) and Postmassage (post-m) test for prostatitis. This simplified, cost and time effective diagnostic technique is suggested for patients with the clinical diagnosis of a chronic prostatitis syndrome and no clinical evidence of urethitis technique: 1. After adequate cleansing of the penis and the foreskin retracted, have the patient provide a midstream urine specimen. Label this specimen pre-m. 2. Perform digital rectal examination to assess the patient's prostate and rigorously massage the prostate toward the midline. 3. Have the patient immediately provide another urine specimen (the first 10ml). Label this specimen post-m. 4. Send the two specimens for microscopy (resuspended post centrifuged specimen) and quantitative culture. Interpretation: 1. Leucocytosis in post-m (> WBC/HPF or 1 log increase in WBC/HPF compared with pre-m test) suggests the diagnosis of prostatitis. 2. Significant bacteriuria in post-m specimen (defined as any bacteria if pre-m specimen sterile or colony count per ml 1 log greater compared with pre-m specimen) suggests bacterial prostatitis. 3. Significant bacteriuria in both pre-m and post-m specimen suggests bacterial prostatitis associated with bacterial cystitis. If confirmation of bacterial prostatitis is required repeat pre-m and post-m cultures after 3 days of nitrofurantoin therapy. 65 Sebha Medical Journal, Vol. 6(1), 2007.
Chronic bacterial prostatitis is a suble disease characterized by relatively asymptomatic periods between episodes of recurrent acute urinary tract infections. It is impossible to be diagnosed by physical examination. Although some patients are asymptomatic, most present with symptoms associated with bacteruria such as dysuria, frequency urgency, low back or perineal discomfort or painful ejaculation with or without hematospermia. The prostate feels normal on palpation and excretory urography and cystoscopy, which are usually unremarkable. 12 This prospective study was undertaken to determine antimicrobial susceptibility pattern of microbes isolated from patients with the clinical diagnosis of prostatitis syndrome in south Libya. Materials and Methods: This prospective study was conducted in El Najah Polyclinic in Sebha, south Libya in the period from October 2003 to September 2006. The pre-massage (Pre-M) and post-massage (post-m) testing technique of prostatitis was employed to investigate patients with the clinical diagnosis of prostatitis. 9-12 After adequate cleansing of the penis, the patient was to provide a midstream urine specimen (pre-m). During collection, the patient began to urinate into the commode and then catches the middle part of the voiding in the specimen container (pre-m). 13 Thereafter digital rectal examination was performed to assess the patients prostate and rigorously massage the prostate towards the mid-line. Then the patient had to provide another urine specimen, the first 10ml (post-m). Muller Hinton agar medium without serum and Oxoid antimicrobial discs were used for quantitative culture and sensitivity testing. 14 Significant bacteriuria was indicated as 10 5 CFU/ml of clean catch midvoid urine specimen. 13 Twelve antimicrobial agents were tested and sensitivity results were then read as susceptible, moderately sensitive and resistant as recommended by the disc manufacturer. 14 Significant bacteriuria in post-m specimen, defined as any bacteria if pre-m specimen was sterile or colony count per ml one log greater compared with pre-m specimen, suggested bacterial prostatitis. Significant bacteriuria in both pre-m and post-m specimen suggested bacterial prostatitis associated with bacterial cystitis (table 2). 9-11 Results: Laboratory specimens were collected from a total of 250 consecutive men with the clinical diagnosis of prostatitis syndrome, in the period from October 2003 to September 2006 in accordance to the pre-massage and postmassage testing technique of proatatitis. The patients' ages ranged from 19 to 82 years with a mean age of 47 years. Eighty-eight (35.2%) patients had bacterial prostatitis. Escherichia coli were isolated from 34 (38.6%), Staphylococcus aureus from 33 (37.5%) and Pseudomonas aeruginosa from 10 (11.36%) patients with bacterial prostatitis (Table 3). Table 3: Micro-organisms isolated from 88 patients with bacterial prostatitis. Micro-organism Number of patients % Escherichia coli 34 38.6 Staphylococcus aureus 33 37.5 Pseudomonas aeruginoza 10 11.36 Neisseria gonorrhoea 4 4.5 Others 7 7.9 Antibiotic susceptibility studies of the isolated E. coli strains indicated that Gentamicin was the most effective agent (73.5%), followed by Nitrofurantoin (70.6%) and Amoxycillin (47.1%). The majority of E. coli strains were resistant to Erythromycin (88%), Tetracycline (76.5%) and Trimethoprim (73.5%), (Table 4). Gentamicin and Nitrofurantoin were equally effective (56.5%) against Staphylococcus aureus followed by Amoxycillin (34.8%). The vast majority of isolated Staphylococcus aureus were resistant to Erythromycin (95.7%), Tetracycline (87%) and Trimethoprim (78.3%), (Table 5) Antibiotic resistance rate among isolated Pseudomonas aerugnosa was very high and only 40% of them were susceptible to Gentamicin (Table 6). All pseudomonas species were resistant to Tetracycline. 66 Sebha Medical Journal, Vol. 6(1), 2007.
Table 4: Antibiotic susceptibility rate of E. coli. Antimicrobial agent Sensitive +++ Moderate Sensitive ++ Resistant Gentamicin 25 (73.5%) 1 (2.9%) 8 (23.5%) Nitrofurantoin 24 (70.6%) 3 (8.8%) 7 (20.6%) Amoxycillin 16 (47.1%) 7 (20.7%) 11 (32.4%) Cephalexin 13 (38.2%) 7 (20.6%) 14 (52.9%) Ampicillin 13 (38.2%) 5 (14.7%) 16 (47.1%) Penicillin 11 (32.4%) 4 (11.8%) 19 (55.9%) Cephaloridine 9 (26.5%) 7 (20.6%) 18 (52.9%) Nalidixic acid 7 (20.6%) 4 (11.8%) 23 (67.6%) Chloramphenicol 5 (14.7%) 5 (14.7%) 24 (70.6%) Trimethoprim 3 (8.8%) 6 (17.6%) 25 (73.5%) Tetracycline 1 (2.9%) 7 (20.6%) 26 (76.5%) Erythromycin 2 (5.9%) 2 (5.9%) 30 (88.2%) Table 5: Antibiotic susceptibility rate of Staphylococcus aureus. Moderate Antimicrobial agent Sensitive +++ Resistant Sensitive ++ Gentamicin 13 (56.5%) 0 (0%) 10 (43.5%) Nitrofurantoin 13 (56.5%) 3 (13%) 7 (30.4%) Amoxycillin 8 (34.8%) 5 (21.7%) 10 (43.5%) Cephalexin 7 (30.4%) 5 (21.7%) 11 (47.8%) Ampicillin 7 (30.4%) 4 (17.4%) 12 (52.2%) Penicillin 5 (21.7%) 2 (8.7%) 16 (69.6%) Chloramphenicol 4 (17.4%) 3 (131%) 16 (69.6%) Nalidixic acid 4 (17.4%) 3 (13%) 16 (69.6%) Cephaloridine 3 (13.0%) 6 (26.1%) 14 (60.9%) Trimethoprim 2 (8.7%) 3 (13%) 18 (78.3%) Tetracycline 0 3 (13%) 20 (87.0%) Erythromycin 1 (4.37%) 0 (0%) 22 (95.7%) Table 6: Antibiotic susceptibility rate of Pseudomonas aeruginosa. Moderate Antimicrobial agent Sensitive +++ Resistant Sensitive ++ Gentamicin 4 (40%) 2 (20%) 4 (40%) Ampicillin 3 (30%) 1 (10%) 6 (60%) Penicillin 3 (30%) 0 7 (70%) Trimethoprim 2 (20%) 1 (10%) 7 (70%) Nitrofurantoin 2 (20%) 0 8 (80%) Nalidixic acid 2 (20%) 0 8 (80%) Amoxycillin 1 (10%) 3 (30%) 6 (60%) Cephaloridine 1 (10%) 1 (10%) 8 (80%) Cephalexin 1 (10%) 1 (10%) 8 (80%) Chloramphenicol 0 2 (20%) 8 (80%) Erythromycin 0 1 (10%) 9 (90%) Tetracycline 0 0 10 (100%) 67 Sebha Medical Journal, Vol. 6(1), 2007.
Ninety per cent of isolated Pseudomonas species were resistant to Erythromycin and seventy per cent to Trimethoprim, (Table 6). Discussion: Understanding the principles of antimicrobial therapy requires a thorough knowledge of both drugs and microbes. If the urologist fails to make the proper diagnosis, the patient's condition can worsen, resulting in hospitalization, sepsis, escalating costs, and, at worst death. Improper diagnosis can prompt the prescription of the wrong antimicrobial, which can alter the sensitivity, increase the nosocomial infection rate in a hospital environment, and, also cause pressure on the community of resistant organisms. Furthermore, sensitivity to all antimicrobials is constantly changing. If physicians are not aware of the change in their particular locale, then they are further increasing the gamble of treatment and the risk of failure resulting in increased costs of the treatment regimen. 15 In the present series, bacterial prostatitis was diagnosed in 88 patients (35.2%) out of 250 patients with the clinical diagnosis of prostatitis syndrome. This finding is supported by the consistent demonstration that 30-40% of prostatitis patients respond to antibiotic therapy. 16-18 In contrast a previous study of prostatitis, and prostatodynia, in 1983, Schaeffer, found that non-bacterial prostatitis was eight times more common than bacterial prostatitis. 19 However, the method of study and criteria of diagnosis of bacterial prostatitis was different from the standardized method employed in this study. Escherichia coli, isolated from 38.6% of patients with bacterial prostatitis, was the most common organism. This is comparable to the report that bacteria causing both acute and chronic bacterial prostatitis in the United States are similar in type and incidence to those that cause simple urinary tract infections, with aerobic gram-negative enteric bacteria, especially E. coli, being the most common. 20,21 Staphylococcus aureus, (37.5%) was the second most common organism. However, great controversy exists as to whether or not other gram-positive bacteria are causative organisms in prostatitis. 22 Coagulase-negative staphylococci which are dismissed by many researchers and clinicians as only urethral contaminants, may in fact be implicated in low-grade inflammation of the prostate gland. 21-31 A large number of pharmacokinetic studies were done on various canine models quantitating antimicrobial diffusion into prostate and from these particular types of studies Trimethoprim, Erythromycin and Quinoline have been described as the most suitable drugs for the treatment of bacterial prostatitis. This is based on the realization that only the non-ionized portion of the drug is lipid-soluble, which is required for the drug transport across the human lipid membranes, such as the prostatic epithelium. Antibiotic susceptibility results of the isolates revealed that the most effective drugs against E. coli and staphylococci were Gentamicin, Nitrofurantoin and Amoxycillin (Table 4-5). Gentamicin was the most effective drug against Pseudomonas followed by Ampicillin and Penicillin (Table 6). On the other hand, the vast majority of prostatic bacterial isolates were resistant to Erythromycin and Trimethoprim. Accordingly, the high resistance rates of the common prostatic bacterial isolates to these agents indicate that the bacterial prostatic syndrome would continue to be a problem in this area. The therapeutic dilemma would be compounded by the fact that antibiotics do not cure chronic bacterial prostatitis consistently. The reason for which does not appear to be the development of bacterial resistance to the antibiotic or the antibiotic levels within the prostate but rather the persistence of hibernating bacterial micro-colonies or biofilms adherent to the ducts or within the corpora amylacea or prostatic calculi within the prostate. 25 In conclusion, the high pattern of prostatic bacterial isolates resistance to Erythromycin and Trimethoprim indicate that treatment of bacterial prostatic syndrome would pose a problem in south Libya. However, Trimethoprim - sulpha methoxazole and the new quinolones were reported to have the bestconfirmed cure rates in recent prospective studies, 29-31 and need to be evaluated in a future study. 68 Sebha Medical Journal, Vol. 6(1), 2007.
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