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E-ISSN: 2808-6724
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1939
THE EFFECT OF CIPROFLOXACIN ON PROSTATE-SPECIFIC
ANTIGEN (PSA)
Andre Dwi Gustiano
1
, Alvarino
2
, Etriyel MYH
3
, Peri Eriad Yunir
4
Medical School of Andalas University, Padang, West Sumatra, Indonesia
Dr. M. Djamil Hospital, Padang, West Sumatra, Indonesia
1
andredwigustiano@gmail.com
2
alvarinouro@gmail.com
3
etriyelmyh@yahoo.com
4
dr.peri.eriad.yunir@gmail.com
ARTICLE INFO
ABSTRACT
Published: November 22
nd
,
2022
Increased PSA levels can be caused by prostate cancer, prostate infection,
and BPH. Several studies report that the use of antibiotics can affect PSA
levels. This study aims to determine the effect of ciprofloxacin
administration in patients with prostate-specific antigen values of 4-10
ng/mL. This was an analytical study with a prospective cohort design. This
study was conducted at Dr. M. Djamil Hospital, Padang starting from July
2022 until October 2022. The sampling technique used non-probability
sampling with consecutive sampling method. The patient was given the
antibiotic ciprofloxacin 2x500 mg for 2 weeks. PSA measurements were
carried out before and after administration of antibiotics. There were 20
subject with an average age of 62.65 years (52-79). The mean of initial PSA
value was 6.53 ng/mL and the final PSA value was 5.76 ng/mL. There was
a significant difference between PSA levels before and after administration
of ciprofloxacin (p=0.000). The use of antibiotics in patients with PSA levels
of 4-10 ng/ml can reduce PSA levels.
Keywords: PSA, antibiotics,
prostate cancer, prostatitis
This work is licensed under CC
BY-SA 4.0
INTRODUCTION
Prostate-specific antigen (PSA) is a serine protease enzyme that is transcriptionally activated
by androgens. PSA level examination is one of the supporting tests that can be done for the
diagnosis and screening of prostate cancer in asymptomatic patients. Examination of PSA levels
can also be carried out for supervision after diagnosis, monitoring of therapeutic responses, and
histological criteria in the stratification of the risk of recurrence (Duffy, 2020; Rebello et al., 2021).
Prostate-specific antigen (PSA) forms in melting the coagulum of seminal fluid after
ejaculation. Once produced by the epithelium of the prostate gland, the PSA will be secreted
through the ductus of the prostate gland. PSA levels may increase due to several risk factors, such
as inflammation or neoplasms. Patients with prostatitis, BPH and prostate cancer are reported to
have elevated PSA levels (David & Leslie, 2022; Moradi et al., 2019).
Prostate cancer is one of the most common cancers found around the world and is the cause
of mortality in men. The incidence of prostate cancer is associated with different geographical
variations (Matsushita et al., 2020). The incidence of prostate cancer is higher in developed
countries than in developing countries. A comparison of these incidents was reported to be 1 in 47
among low- to middle-income countries. Meanwhile, the comparison of prostate cancer incidence
in the country is 1 in 6. It is reported that the incidence of prostate cancer in Western countries is
6 times that of non-Western countries (Leslie et al., 2022; Pernar et al., 2018).
The prevalence of new cases and mortality caused by prostate cancer has increased from year
to year. Reports in 2018, newly diagnosed prostate cancer cases were 1.2 million cases with
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2022
360,000 deaths (Matsushita et al., 2020). In 2020, the number of new cases reported was 1,414,249
cases with 375,000 deaths (Leslie et al., 2022). The United States reported the number of new
cases of prostate cancer during the period 2003-207 which was 3,087,800 cases (Siegel et al.,
2020).
The etiology and risk factors for prostate cancer are age, ethnicity, obesity, and family
history. The incidence of prostate cancer will increase according to age. The development of
prostate cancer incidence will increase in patients over 55 years of age. Ethnicity is genetically
related to prostate cancer where it is reported that there are 180 genetic loci. By race or ethnicity,
the incidence of prostate cancer in the United States is more prevalent in black males and 2.4 times
greater than in whites (Pernar et al., 2018).
Prostate cancer screening using PSA levels can be done for early detection of prostate cancer.
However, elevated PSA levels are not only affected by diseases other than prostate cancer, such
as infections and BPH. Nordström et al. (2018), conducting a PSA density analysis with the
incidence of prostate cancer. PSA density results of 0.10 ng/mL 2 and 0.15 ng/mL
2
can detect the
incidence of prostate cancer by 77% and 49%, respectively. Men with prostate cancer risk factors
are recommended to have PSA levels checked. The combination of PSA levels with risk factors
as well as clinical findings can increase suspicion of diagnosis and determine subsequent actions
(Gandaglia et al., 2019).
Prostatitis is an inflammatory prostate disease that reports 15-25% of urological clinical
visits. Based on the National Institutes of Health (NIH), prostatitis can be grouped into categories
I through IV. Inflammation of the prostate epithelium will cause damage to epithelial cells (Kanani
et al., 2021; Khan et al., 2017). This situation will cause the PSA to exit towards the extracellular
space and be absorbed towards circulation (Sfanos et al., 2018).
Some studies report that the use of antibiotics can affect PSA levels. The use of ciprofloxacin
2 times 500 mg for 2 weeks in patients with PSA levels of >10 ng/mL may significantly lower
PSA levels (Karakose, Yuksel, et al., 2015). Antibiotic therapy for 4 weeks in patients with
suspected prostate cancer who had PSA levels of 4 to 10 ng/mL decreased significantly (p<0.001)
(H et al., 2017). The use of antibiotics in patients with elevated PSA levels of >4 ng/mL may avoid
prostate biopsy examinations. The decrease in PSA levels with the use of antibiotics varies from
17% to 80% of cases (Taha et al., 2020). Therefore, researchers are interested in conducting
research on the effect of antibiotic administration on PSA levels of patients with suspected prostate
cancer.
Based on the description in the background above, the purpose of this study was to determine
the effect of ciprofloxacin administration in patients with prostate-specific antigen values of 4-10
ng/mL.
METHOD
This study is an analytical study with a prospective cohort design to determine the effect of
giving ciprofloxacin in patients with a prostate-specific antigen value of 4-10 ng / mL in the sample
treatment group. The data used is sourced from data on the examination process carried out on
The Effect of Ciprofloxacin on Prostate-Specific Antigen (PSA)
1941 | I n d o n e s i a n J o u r n a l o f M u l t i d i s c i p l i n a r y S c i e n c e , 2 ( 2 ) , N o v ,
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patients with PSA levels of 4-10 ng/mL. This research was conducted at RSUP Dr. M. Djamil
Padang which has an accredited laboratory starting from July 2022 to September 2022.
The population of this study was patients with PSA levels of 4-10 ng/mL in the environment
of RSUP DR. M. Djamil, in the study time span. The sampling technique in this study used non-
probability sampling with the consecutive sampling method, namely all patients with a PSA value
of 4 -10 ng/mL met the research criteria included in the study until the number of samples was met
by 20 samples. The sample size is calculated based on the sample size formula for hypothetical
testing of the mean difference before and after treatment:
Information:
Z : Patent derivatives alpha = 1.59
S : Standard Deviation = 2.8
d : set 1
Based on the results of the sample calculation above, a minimum number of samples of 20
samples was obtained. The study used primary data where data was collected through assessing
PSA levels before and after antibiotics for two weeks.
The stages of this research include:
1) Preparatory Stage: This preparation stage is an activity to carry out patients who have
PSA levels of 4-10 ng/mL. Samples were taken taking into account inclusion and
exclusion criteria.
2) Implementation Stage: This stage of implementation is an activity to collect PSA level
data.
3) Final Stage of Research: The final stage of this research is the activity of processing and
analyzing research data and compiling and duplicating research reports. The analysis here
includes univariate analysis (Mean value and standard deviation (SD) of PSA levels
calculated in the antibiotic and non-administration groups) and statistical analysis (The
collected data is edited, coding, and entered into a computer file, conducted statistical
analysis with SPSS software. The anbitiotic test given to patients suspected of prostate
cancer to PSA levels assessed after the intervention was carried out with the pair T-Test).
For research ethics, this research was conducted using humans as research subjects. The
permit was granted by the Research Ethics Commission of the Faculty of Medicine, Andalas
University, Padang.
RESULT AND DISCUSSION
This research is a type of analytical study with a prospective cohort design. The study was
conducted at Dr. M. Djamil Padang Hospital during July 2022 to October 2022. The sample
The Effect of Ciprofloxacin on Prostate-Specific Antigen (PSA)
1942 | I n d o n e s i a n J o u r n a l o f M u l t i d i s c i p l i n a r y S c i e n c e , 2 ( 2 ) , N o v ,
2022
collected at the end of the study was 20 people who met the inclusion criteria and did not have
exclusion criteria. Data on the characteristics of the study subject and the level of PSA were taken
before the intervention. After administration of the antibiotic ciprofloxacin 2x500 mg to the
patient, the PSA level examination is carried out again for analysis.
Patient Characteristics
Based on Table 1, it is known that the average age of the subjects of this study was 62.65
years with the youngest age being 52 years and the oldest age being 79 years. The average initial
PSA value of the subjects of this study was 6.53 ng/mL and the final PSA value was 5.76 ng/mL.
The smallest value of PSA levels at the end of the study was found to decrease but the maximum
value also increased so that the min-max range after treatment was larger.
Table 11. Characteristics of the Subject of Research
Characteristics
Mean
Min – Max
SD
Age
First PSA
Final PSA
62,65
6,53
5,76
52 – 79
4,19 – 9,34
2,97 – 10,17
6,8
1,6
2,0
Evaluation of Changes in PSA Levels with Ciprofloxacin Administration in Patients with
Prostate-Specific Antigen Values of 4-10 ng/mL
Based on Table 2, it is known that the difference in the average PSA value of the study
subjects before and after the administration of ciprofloxacin was 0.77. Based on the normality test
with the Shapiro-Wilk test, it is known that the data is normally distributed. Statistical analysis
was carried out with a Paired sample T-test with the results known that there was a significant
difference between PSA levels before and after ciprofloxacin administration (p = 0.000).
Table 2. Comparison of PSA Levels Before and After Ciprofloxacin Administration at PSA
Levels
Examination
Level of PSA
P-Value
Mean
SD
Before
After
6,53
5,76
1,6
2,0
0,000
Characteristics of the Subject of Research
In this study, a total sample of 20 people was obtained with an average age of 62.65 years
with the youngest age being 52 years and the oldest age being 79 years. These results are similar
to those found in a study by Serretta et al who conducted a study on 99 patients with PSA levels
of 4-10 ng/mL where the average age was 65 years with a wider range of 48-83 years. In this study,
a follow-up biopsy was performed and the average age was obtained between patients with prostate
cancer and without prostate cancer (Serretta et al., 2008). Other studies were also conducted by
The Effect of Ciprofloxacin on Prostate-Specific Antigen (PSA)
1943 | I n d o n e s i a n J o u r n a l o f M u l t i d i s c i p l i n a r y S c i e n c e , 2 ( 2 ) , N o v ,
2022
Karakose et al. (2015) in 96 patients and obtained the average age in the study subjects with PSA
levels of 4-10 ng / mL was 61.6 ± 5.7 (51-75) years. In this study, patients came in with complaints
of urination. These complaints arise data caused by obstruction that occurs as a result of enlarged
prostate mass. Enlargement and abnormalities of the prostate period often occur in the age range
of 60-70 years. In men with advanced age, significant tissue remodeling occurs inside the prostate.
Abnormal prostate growth at this age is the result of a disturbed balance between apoptosis activity
and proliferation with a net reduction of apoptosis activity. Histological analysis showed a
decrease in apoptosis activity in glandular and basal epithelial cells of the prostate. In addition, in
malignant suspicions, enlarged prostate can occur as a result of excessive cell proliferation which
also causes PSA levels to increase above normal (Putra et al., 2016). Data from the cancer statistics
center get the average age of diagnosis of prostate malignancy is 66 years (American Cancer
Society, n.d.).
The average initial PSA value of the subjects of this study was 6.53 ng/mL with a min-max
value of 4.19 – 9.34 and the final PSA value was 5.76 ng/mL with a min-max value of 2.97 - 10.17.
Overall, there was a decrease in the PSA value of 0.77 ng/mL. However, judging from the min-
max value of the sample, there was a decrease and increase in the PSA value in patients, with some
samples decreasing until they became normal and some reaching the limit past 10 ng/mL. A similar
study was conducted by Buddingh et al. in 2018 in a systematic review to assess evidence of
antibiotic therapy in patients with type IV (asymptomatic) prostatitis with respect to reduced PSA
levels and discrimination between prostate cancer and inflammation. In this study, the initial PSA
levels were mostly also in the range of 4-10 ng/mL. In total, the study reported 1011 patients with
type IV prostatitis with 926 treated with antibiotics. Normalization of PSA was seen after antibiotic
treatment in 33.2% of patients. Three of these studies showed a lower prevalence of prostate cancer
in patients whose PSA became normal (Buddingh et al., 2018).
Changes in PSA Level Values with Ciprofloxacin Administration in Patients with Prostate-
Specific Antigen Values of 4-10 ng/mL
Prostate specific antigen (PSA) is a serine protease enzyme produced by the columnar
epithelium of prostate tissue. Locally, PSA prevents seminal coagulation by breaking down these
proteins into smaller peptides and thus, helps facilitate impregnation. PSA production increases
with age. Serum PSA levels are not specific to prostate cancer, let alone aggressive prostate cancer
that may require intervention in the future. In addition, there is no PSA level that reliably
guarantees that prostate cancer is present or absent (David & Leslie, 2022). Prostate inflammation
is another cause of increased PSA in men referred for suspected prostate cancer (Buddingh et al.,
2018). In addition, PSA levels may increase due to several reasons such as trauma, ejaculation,
and rectal plugging and action on the urethra. Other non-cancerous etiologies that can cause an
increase in PSA levels, such as benign prostatic hyperplasia (Atalay et al., 2017). The
inflammatory influence has to do with the intensity and degree of epithelial damage so that this
causes an increase in the detected levels of PSA (Rajakumari et al., 2019).
The Effect of Ciprofloxacin on Prostate-Specific Antigen (PSA)
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Despite the controversy surrounding the value of antibiotics in reducing higher PSA levels,
some urologists in daily practice often prescribe antibiotics before prostate biopsy to men with
newly elevated PSA levels. The reduction of PSA levels after the administration of antibiotics can
identify patients whose prostate biopsy can be avoided (Özman O & Talat Z, 2019; Taha et al.,
2020).
In this study, the administration of the antibiotic ciprofloxacin 2 x 500 mg for 2 weeks was
carried out in patients who came with complaints of urinary disorders and had PSA levels of 4-10
ng/mL. After antibiotics, there was a decrease in PSA levels by 0.77 ng/mL even though overall
PSA levels did not reach normal, namely 5.76 ng/mL. In this study, a significant relationship was
also found between PSA levels before and after ciprofloxacin administration.
Similar results to this study were obtained by Toktas et al. (2013) who conducted the study
on patients aged 45-70 years with PSA results of 2.5 – 10 ng/mL. In patients administered oral
antibiotic levofloxacin 500 mg 1 time per day for 21 days. In this study, there was a decrease in
PSA levels in patients with an initial average of 5.31 ng / ml to 4.69 ng / ml and statistical analysis
showed this change was significant. In this study, a follow-up biopsy was also carried out and
concluded that antibiotic treatment given to patients with PSA levels between 2.5 and 10 ng/mL
could be useful before the decision to perform TRUS guided prostate biopsy but this only applies
in a limited subgroup, namely the group that experienced a decrease in PSA levels to below the
threshold value.
Similar results were also found by Rajakumari et al. (2019) which assessed 50 patients aged
50-80 years with elevated PSA levels (4-20 ng/mL). In this study, antibiotics were given longer,
namely 6 weeks and found 20/50 experienced a decrease in PSA levels below 4 ng/mL, 18 cases
fell but still in the range of 6-10 ng/mL, 8 cases only decreased by 1-2 ng/ml and 4 cases did not
decrease PSA levels. In this study, 20 cases that experienced a decrease in PSA to below 4 ng/mL
were subjected to annual rectal plug and PSA examination, the remaining 30 people with PSA
levels still above 4 ng/mL underwent biopsy. In 18 cases with decreased PSA levels, 7 cancer
biopsy results were obtained, 4 cases of BPH with prostatitis, 3 cases of prostatitis, 2 cases of BPH
and 1 case of BPH with intraepithelial neoplasia and 1 case with granulomatous prostatitis. In 8
cases that only dropped slightly, 3 were known to have cancer, 2 people with prostatitis, 3 people
with prostatitis with BPH and 1 person had BPH and of the 4 cases that did not experience a
decrease at all after being given antibiotics, there was evidence of cancer in 1 case, prostatitis in 1
case, BPH and prostatitis in 1 case and prostatitis xanthogranuloma in 1 case.
Serretta et al. (2008) conducted a similar study followed by follow-up biopsies in patients to
assess whether a decrease in PSA could distinguish patients with benign abnormalities in the
prostate and malignancy, Ninety-nine patients received ciprofloxacin for 3 weeks and 59 of them
showed a decrease in PSA. Histologic examination detected small foci of prostatitis in 65% of
cases and carcinoma was found in 40 and 20.3% of patients with unchanged or decreased PSA (P
= 0.03). No cancer is detected if the PSA decreases below 4 ng/mL or more than 70%. In this
study, it was concluded that biopsy can be postponed with a low risk of cancer, if the PSA
decreases by more than 70% or below 4 ng/ml.
The Effect of Ciprofloxacin on Prostate-Specific Antigen (PSA)
1945 | I n d o n e s i a n J o u r n a l o f M u l t i d i s c i p l i n a r y S c i e n c e , 2 ( 2 ) , N o v ,
2022
Ozman et al. (2019) conducted a similar study in Turkey but found no significant association
with changes in PSA values. In this study, oral levofloxacin was given for 2 weeks and a PSA re-
examination was carried out with 64 of the 136 subjects who experienced a decrease in PSA levels.
After that, a biopsy was performed on the patient and the group was divided into two, namely the
cancer group and the benign abnormality group (From the biopsy results). As a result, the first
PSA value (5.81 ± 1.37) was lower in the cancer-detected group than in the other group (6.43 ±
1.82) but the difference was not statistically significant. In addition, there was also no difference
in changes in PSA values between the cancer group and the benign abnormality group.
Karakose et al also in 2015 also got different results where the administration of
ciprofloxacin 500 mg twice a day for 2 weeks in the group of patients with PSA levels of 4-10
ng/mL did not cause a significant decrease in PSA and a new decrease occurred in the PSA group
with higher values of >10 ng/mL (Karakose, Bilgehan Yuksel, et al., 2015).
Some researchers have found that antibiotic treatment can reduce the increase in PSA caused
by inflammation and help reduce unnecessary biopsies (Rajakumari et al., 2019; Serretta et al.,
2008; Toktas et al., 2013). This is similar to the results found in this study. In contrast, others have
reported that antibiotic treatment has no significant effect on PSA levels, and lower PSA levels
after antibiotic treatment do not mean a reduced risk of prostate cancer (al Jalham et al., 2016;
Fandella et al., 2014; Karakose, Bilgehan Yuksel, et al., 2015; Özman O & Talat Z, 2019). The
administration of antibiotics for 2 weeks in this study was based on a prospective experiment that
showed a decrease in PSA reached the "plateau" stage on day 7. The type of antibiotic used is
usually based on local sensitivity and quinolones are the most used type (Özman O & Talat Z,
2019; Taha et al., 2020).
CONCLUSION
The study was conducted on 20 subjects with a median age of 62.65 years. The average initial
PSA value of the subjects of this study was 6.53 ng/mL and the final PSA value was 5.76 ng/mL.
There was a significant difference between PSA levels before and after ciprofloxacin
administration with a p value of 0.000.
Further research is expected to be conducted to assess the relationship of PSA reduction after
antibiotic administration with patient biopsy results as well as the magnitude of the decrease in
PSA levels associated with low cancer probability. This study was used as the basis for the
management of symptomatic patients with PSA levels of 4-10 ng / ml to avoid unnecessary biopsy.
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