Treatment of chronic bacterial prostatitis with amikacin through anal submucosal injection

Wei-Lie HU, Shi-Zhen ZHONG1, Hui-Xu HE

Asian J Androl  2002 Sep; 4:  163-167             

Keywords: prostate; prostatitis; therapy; amikacin

Abstract

Aim: To assess the efficacy and safety of anal submucosal injection (ASI) of amikacin in chronic bacterial prostatitis (CBP). Methods: Fifty male outpatients with CBP were randomly divided into two groups. Thirty cases of ASI group were given amikacin 400 mg daily by ASI for ten times and the other twenty cases of intramuscular injection (IM) group were given the same drug daily by IM. All patients were evaluated with NIH-Chronic prostatitis symptom index (NIH-CPSI), the bacteria culture of the expressed prostate secretion (EPS), proctoscopic examination, rectal biopsy and the clinical manifestation were checked at pretreatment and on day 7 and 90 after cessation of therapy. Results: The cure rate, apparent effective rate and effective rate of ASI group and IM group were 33.3 % vs 5 % (P<0.05), 43.3 % vs 10 % (P<0.05) and 16.7 % vs 20 % (P>0.05), respectively. The score of NIH-CPSI in both of ASI group and IM group decreased significantly 7 days after cessation of therapy, both ASI and IM of amikacin could relieve symptoms within a short time. However, 3 months after cessation of therapy the score of NIH-CPSI in ASI group continued down in spite of no significant differences compared with 7 days after cessation of therapy, but the score of IM group was rebound nearly closed to level of pretreatment at 23.88.5 and significantly higher than that of ASI group. The amount of white blood cell (WBC) of EPS in ASI group increased slightly at 7 days after cessation of therapy without significant difference with pretreatment (P>0.05), but it significantly decreased at 3 months after cessation of therapy, the amount of WBC of EPS in ASI group was lower than that of IM group at 3 months after cessation of therapy (P<0.05). Proctoscopic examination of anal canal were normal after ASI therapy and the rectum biopsy showed no obvious histopathologic abnormality at the site of injection except mild focal submucosal infiltration of lymphocytes and plasma cells at 7 days after cessation of therapy which disappeared on 3 months after cessation of therapy. All patients had no evident complications. Conclusion: ASI could be recommended as a new safe, effective, painless method of antibiotics administration in the treatment of CBP.

Chronic prostatitis is a common disease in men and its therapeutic efficacy has been unsatisfactory [1]. Chronic bacterial prostatitis (CBP) is a kind of chronic prostatitis with a relatively low occurrence of about 5 % [2] and its curative approach is also disappointing.

Antibacterial agent is the major therapy for CBP, however, it fails to diffuse in adequate concentrations from the plasma into the prostate tissue irrespective of given by oral, intramuscular or intravenous route. In order to increase the drug concentration in prostate, antibiotics have been injected into the prostate, urethra or vas deferens. Direct injection into prostate may induce hemospermia, hematuria, pain and prostatic hyperplasia. Injection through urethra may cause bleeding, discomfort and retrograde infection, and injection through vas deferens may cause bleeding, infection, and vas deferens stricture and obstruction [3]. Thus urologists all over the world are endeavoring to find out new and safe approaches.

Anal submucosal injection (ASI), founded by Shafik[4] in 1985, was at first used in pelvic malignancies, in-cluding rectal cancer [5], bladder cancer [6,7], prostatic cancer [8,9] and cervical cancer [10] with good effectiveness and negligible side effects. In 1991 Shafik also applied ASI with gentamycin to treat 11 cases of CBP and all patients were satisfactory cured without recurrence in the observation period of six months [11]. The present study was designed to evaluate the method by the treatment of CBP patients with amikacin, which is regularly used in the treatment of gram-negative bacterial infection, applied through ASI.

2 Materials and methods

2.1 Patients and treatment

From Dec. 1999 to Oct. 2001, fifty male outpatients with CBP, 25 to 45 (average 33) years of age, with a history of CBP for 3 months to 6 years (mean 12.2 months), were recruited. They were randomly divided into two groups, 30 patients in the ASI group and 20 in the intramuscular (IM) group. The bacterial culture of expressed prostate secretion (EPS) of all the patients were sensitive to amikacin. The ASI group was given daily ASI of 400 mg amikacin for ten days, and the IM group was given by IM of amikacin daily for 10 days with the same dosage.

Amikacin 400 mg is diluted with 2 mL of normal saline. A 10 mL capacity syringe adapted with a # 6 needle is used for injection. With the patient at the lithotomy or left lateral position, a proctoscope is introduced, the anal canal is inspected, and the pectinate line is identified. The drug will be injected into the anal submucosa of the anterior wall above this line. The mucosa at the proposed site of injection is swabbed clean and disinfected with 75 % alcohol. The needle is then inserted obliquely through the mucosa into the submucosa and a small amount of the amikacin solution is injected. If the mucosa balloons up with an edematous wheal, this indicates that the fluid has been spreaded in the submucous plane as desired. If no wheal is produced, the needle is too deep and should be gradually withdrawn with simultaneous, repeated injections of minimal amounts of the fluid until the effect described is achieved. A dead white tinge at the injection site signifies that the fluid is being injected into the muco-sa. When the proper submucosal plane is reached, the rest of the solution is injected.

2.3 Observation

The patients were evaluated with NIH-Chronic prostatitis symptom index (NIH-CPSI) [12], in addition to routine physical examination, bacteria culture of EPS and side effect assessment on pretreatment, day 7 and 90 after cessation of therapy. During the observation period, the anorectum was examined daily. The ASI site of ten patients was biopsied on pretreatment, and days 7 and 90 after cessation of therapy. The biopsy specimens were preserved in 10 % formaldehyde solution, stained with hematoxylin and eosin (HE) and examined under a light microscope.

2.4 Assessment criteria of therapy

The patients were assessed 3 months after cessation of therapy and were categorized into 3 classes:

2.4.1 Cured:
(a) Clinical symptoms disappeared;
(b) Number of white blood cell (WBC) in EPS less than 10/high power field (hpf);
(c) Bacterial culture of EPS negative.

2.4.2 Effective:
(a)Clinical symptoms alleviated;
(b) Number of WBC in EPS less than 10/hpf;
(c) Bacterial culture of EPS negative.

2.4.3 Improved:
(a) Clinical symptoms alleviated;
(b) Number of WBC in EPS decreased, but more than 10/hpf;
(c) Bacterial culture of EPS negative.

2.4.4 Ineffective:
(a) Clinical symptoms unchanged or aggravated;
(b) Number of WBC in EPS unchanged or increased;
(c) Bacterial culture of EPS positive.

Statistical analysis was performed by the chi square test and the Mann Whitney U-test. P<0.05 was considered significant.

As can be seen from Table 1, the cure rate and the effective rate are significantly higher (P<0.05) in the ASI than in the IM Group and the ineffective rate significantly lower (P<0.05) in the ASI than in the IM Group.

Table 1. Therapeutic effect assessed 3 months after cessation of therapy. ^bP<0.05, compared with IM group.

Table 2 showed the NIH-CPSI scores in the two groups. They were similar in the two groups before treatment. In the ASI group, the NIH-CPSI score had a consistent decrease (P<0.05) both at 7 days and 3 months after cessation of therapy. Meanwhile in the IM group it only showed a temporary decrease at 7 days after cessation of therapy. Thus there was a significant difference (P<0.05) in the scores between the ASI and IM groups 3 months after therapy.

Table 2. NIH-CPSI scores in ASI and IM groups. ^bP<0.05,compared with pretreatment. ^eP<0.05,compared with ASI.

The number of WBC in EPS in the ASI group was slightly (P>0.05) increased at 7 days after therapy compared with the pretreatment level, however it was significantly decreased (P<0.05) at 3 months after therapy compared with pretreatment or 7 days after therapy. The IM group showed no significant changes either at 7 days or 3 months after therapy (P>0.05). Moreover, the number of WBC in EPS in the ASI group was significantly lower (P<0.05) than that in the MI group at 3 months after cessation of therapy (Table 3).

Table 3. Comparison of WBC in EPS between ASI and IM groups.

Before therapy the bacterial culture of the ASI group included 4 Staphylococci haemolyticus, 3 Staphylococci aureus, 1 Enterococci, 6 E.Coli, 5 Pseudomonas aerugi-nosa, 4 Krebsiella, 2 Pseudomonas cepacia, 3 Entero-bacter, 1 Acinetobacter calcoaceticus and 1 Citrobacter freundii; in the IM group, 3 Staphylococci haemolyticus, 1 Staphylococci aureus, 1 Enterococci, 4 E.Coli, 4 Pseudo-monas aeruginosa, 2 Krebsiella, 2 Pseudomonas cepacia, 1 Enterobacter, 1 Acinetobacter calcoaceticus, 1 Citro-bacter freundii. All bacteria were sensitive to amikacin.

At 3 months after cessation of therapy, the bacterial culture in the ASI group was 28 negative and 2 positive and those for the IM groups was 7 negative and 13 positive. The data were significantly different between the two groups (P<0.05). The culture results after treatment were 2 Pseudomonas cepacia in the ASI group, while in the IM group, there were 1 Staphylococci haemo-lyticus, 1 taphylococci aureus, 1 Enterococci, 2 E.Coli, 2 Pseudomonas aeruginosa, 2 Krebsiella, 2 Pseudomonas cepacia, 1 Enterobacter and 1 Citrobacter freundii.

Naked eye examination of the rectum revealed no ulcer, masses, necrosis or infection. Only 8 cases of ASI group had a slight congestion at the injection site on the third or fourth day after treatment that subsided thereafter. Microscopic examination of the rectal biopsy specimen showed no obvious histopathologic abnormality at the site of injection except a mild focal submucosal infiltration of lymphocytes and plasma cells at 7 days after therapy, which was not found at 3 months after therapy (Figures 1, 2, 3).

Figure 1. HE staining of rectal biopsy specimen before ASI (magnifi-cation 100)
Figure 2. H E staining of rectal biopsy specimen on 7 days after one course of ASI (magnification 100)
Figure 3. HE staining of rectal biopsy specimen on 3 months after one course of ASI (magnification 100)

The study showed no obvious abnormal clinical reaction and complications in all patients. Three patients of ASI group passed feces covered with slight blood staining after the first injection. Five patients complained of desire of bowel movement just after injection on the first two days of ASI. All symptoms disappeared soon without the need of therapeutic interruption.

Antibiotics, which could kill bacterial inside the prostate in condition of high drug concentration, is the major treatment for CBP. However, it was very difficult to get enough concentration in prostate through regular drug administration such as oral, intramuscular or intravenous method mainly because of the failure of most antibiotics to diffuse from the plasma to the prostatic fluid; this has been shown to be the main cause of recurrence and incurability of CBP in both clinical and experimental studies [1]. So how to increase the antibiotic concentration in the prostate was a very important problem in the treatment of CBP.

Gentamicin through ASI is reported to be successful in the treatment of 11 patients with chronic bacterial prostatitis, which seems to be due to the high drug concentration in the prostate [11]. An experimental study has shown that after injection of 14C-labelled misonidazole (a radiation sensitizer) into the anal submucosa, the prostate showed a concentration of the drug as high as three times of the serum level [13]. Our results showed that cure of CBP is the major treatment for CBP could be achieved by ASI of amikacin, to which the organisms in EPS were sensitive. After one course of therapy, the cure rate and the apparent effective rate of the therapy were 33.3 % and 43.3 %, respectively, which was significantly higher than that of the IM group (5 % and 10 %, respectively).

The route adopted by the drug to reach prostate from the ASI has been clarified. It was shown that 2-6 sizable hemorrhoidogenital veins connected the hemor-rhoidogenital region with the vesico-prostatic plexus. They are unidirectional which transmit blood from the region to the plexus but not in the reverse direction [4]. When amikacin was injected into the anal submucosa, it was absorbed by the hemorrhoidal plexus of veins and lymphatics and then passed through the hemorrhoidogenital vessels to the prostatic plexus, reaching the prostate at a high concentration.

The score of NIH-CPSI in both the ASI and the IM groups decreased significantly 7 days after the course of therapy. Both ASI and IM injection of amikacin could relieve the symptoms within a short time. However, 3 months after the course of therapy the score of NIH-CPSI in the ASI group remained at the level with no significant differences compared to 7 days after therapy, but the score of the IM group was rebounded nearly closed to the pretreatment level at 23.8 8.5, which is significantly higher than that of the ASI group.

Our results showed that no significant complications were encountered with ASI of amikacin in all patients. There were a few patients with mild complaints, but all disappeared after 1-3 hours without any therapeutic interruption. The procedure is simple and painless, as the anal mucosa above the pectinate line is insensitive to pain stimuli. Microscopic study of all stained biopsy specimens showed only mild changes that soon disappeared. The mild tissue inflammatory reaction may be the result of chemical stimulation induced by amikacin.

To summarize, our preliminary results demonstrate that ASI of amikacin is effective in the treatment of CBP. It could be recommended as a new, safe, effective and painless method in the treatment of CBP.

References

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Correspondence to: Dr Wei-lie HU, Department of Urology, the General Hospital of Guangzhou Military Area, Chinese People's Liberation Army, Guangzhou, China.
E-mail: weiliehu@hotmail.com
Received 2002-04-16      Accepted 2002-08-02