Fphar 11 00504

REVIEW
published: 30 April 2020

doi: 10.3389/fphar.2020.00504
Pharmacological Interventions for

Bacterial Prostatitis
Situ Xiong 1, Xiaoqiang Liu 1,2, Wen Deng 1,2, Zhengtao Zhou 1,2, Yulei Li 1,2, Yechao Tu 1,
Luyao Chen 1, Gongxian Wang 1,2 and Bin Fu 1,2*
1 Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China, 2 Jiangxi Institute of Urology,
Nanchang, China
Prostatitis is a common urinary tract condition but bring innumerable trouble to clinicians in
treatment, as well as great financial burden to patients and the society. Bacterial prostatitis
(acute bacterial prostatitis plus chronic bacterial prostatitis) accounting for approximately
20% among all prostatitis have made the urological clinics complain about the genital and
urinary systems all over the world. The international challenges of antibacterial treatment
(emergence of multidrug-resistant bacteria, extended-spectrum beta-lactamase-
producing bacteria, bacterial biofilms production and the shift in bacterial etiology) and
the transformation of therapeutic strategy for classic therapy have attracted worldwide
attention. To the best of our knowledge currently, there is not a single comprehensive
review, which can completely elaborate these important topics and the corresponding
Edited by: treatment strategy in an effective way. This review summarizes the general treatment
Hao Hu, choices for bacterial prostatitis also provides the alternative pharmacological therapies for
University of Macau, China
those patients resistant or intolerant to general treatment.
Reviewed by:
Xiuping Chen, Keywords: bacterial prostatitis, multidrug-resistant E. coli, bacterial biofilms, E. faecalis–Enterococcus faecalis,
University of Macau, China Fosfomycin, phage therapy, plant extracts, combination therapy
Hanna Evelina Sidjabat,
Griffith University, Australia
*Correspondence:
Bin Fu INTRODUCTION
urofbin@163.com
Prostatitis is a common but bothersome urinary tract disease in urological practice that annoys
Specialty section:
patients and urologists worldwide. The incidence rate of prostatitis just follows those of prostate
This article was submitted to cancer (PCA) and benign prostate hyperplasia (BPH) in all male urinary tract conditions. Prostatitis
Pharmaceutical Medicine and may be the most prevalent urinary tract disease in patients below 50 years old (Collins et al., 1998;
Outcomes Research, Schaeffer, 2006). According to the statistics, nearly 16% men reported a history of prostatitis at some
a section of the journal point in their lives, and prostatitis makes up nearly 25% of urologist visits globally (Collins et al.,
Frontiers in Pharmacology
1998; Khan et al., 2017). The global annual cost for primary diagnosis and management is a
Received: 16 December 2019 stupendous sum (over $84 million), excluding medical expenditure and cost of the lost productivity,
Accepted: 31 March 2020 and appears to increase with time (Pontari et al., 2007). High cost brings invisible economic pressure
Published: 30 April 2020
to patients and the society.
Citation: The National Institutes of Health (NIH) has divided prostatitis into four categories via clinical
Xiong S, Liu X, Deng W, Zhou Z, Li Y, characteristics, including acute bacterial prostatitis (ABP) (category I), chronic bacterial prostatitis
Tu Y, Chen L, Wang G and Fu B (2020)
(CBP) (category II), chronic prostatitis/chronic pelvic pain syndrome (CPPS) (category III), and
Pharmacological Interventions
for Bacterial Prostatitis.
asymptomatic inflammatory prostatitis (category IV) (Krieger et al., 1999). The most common
Front. Pharmacol. 11:504. among prostatitis is category III, which affects nearly 90% of patients diagnosed with prostatitis.
doi: 10.3389/fphar.2020.00504 Although the prevalence rate of bacterial prostatitis (approximately 20% of all prostatitis cases) is
Frontiers in Pharmacology | www.frontiersin.org 1 April 2020 | Volume 11 | Article 504

Xiong et al. Pharmacological Interventions for Bacterial Prostatitis
not the highest in the four categories, ABP carries potential risk (Cryptococcus, Salmonella, and Candida), and Mycobacterium
of critical morbidity from abscess, sepsis, and septic shock, if tuberculosis also reportedly cause ABP, especially among
insufficiently managed. CBP is particularly prone to relapse, sexually active and immunocompromised patients (Brede and
which could lead to decreased libido, erectile dysfunction, and Shoskes, 2011; Nagy and Kubej, 2012; Gill and Shoskes, 2016).
premature ejaculation, all of which may severely affect the quality
of life and mental health of patients. In addition, the increasing Evaluation
difficulty of antibacterial treatment (emergence of multidrug- Serum laboratory assessment for ABP generally reveals elevated
resistant bacteria and extended-spectrum beta-lactamase (ESBL)- inflammatory markers, such as white blood cells, neutrophils, C-
producing Escherichia coli, bacterial biofilms production, and shift reactive protein, and erythrocyte sedimentation rate (Sharp et al.,
in bacterial etiology) and the transformation of therapeutic 2010). In a previous study, white blood cells higher than 18,000
strategy have attracted worldwide attention. per mm3 (18 * 109/L) and blood urea nitrogen level higher than
In this article, we focused on bacterial prostatitis (categories I 19 mg/dl (6.8 mmol/L) are independently associated with severe
and II), with an emphasis on current general pharmacological ABP cases (Yazawa et al., 2013). Approximately 70% of patients
therapy regimens, new international therapeutic challenges, and show abnormally elevated prostate-specific antigen (PSA) caused
alternative pharmacological therapeutic strategies for patients by the inflammatory destruction of epithelial cells in the prostate
who are resistant or intolerant to general treatment. We aimed to ducts. However, this condition sometimes should be
provide clinicians with new ideas in treating patients with differentiated from PCA (Ludwig, 2008). Elevated PSA levels
complex bacterial prostatitis and offer patients the hope of would decline to normal after 1–2 months of treatment; if not,
overcoming the disease. PCA should be considered (Ludwig, 2008; Sharp et al., 2010;
Brede and Shoskes, 2011). Routine urine tests often detect
positive leukocyte count. The Meares–Stamey two-glass or
four-glass test is not recommended for men with probable
ABP (NIH CATEGORY I) ABP, because prostatic massage as aggressive prostate
ABP is a prostatic bacterial inflammation that causes pelvic palpation can release bacteria and inflammatory cytokines,
pain, systemic symptoms (fever, chills, nausea, and vomiting), thereby increasing the potential risk of bacteremia, and
and voiding symptoms (frequency, urgency, odynuria, dysuria, subsequently, sepsis (Coker and Dierfeldt, 2016). Less than 2%
and urinary retention in severe cases) (Krieger et al., 1999). A of men with ABP develop prostatic abscess. Patients who remain
tender, swollen, and hot prostate is almost always tangible in febrile after 36 h or whose symptoms do not improve with
rectal examination. The incidence peaks of ABP are in males antibiotics should be evaluated for prostatic abscess. Non-
20–40 years old and those older than 70 years old (Roberts contrast computed tomography (CT) scan, magnetic resonance
et al., 1998). imaging (MRI) of the pelvis, and transrectal prostatic
ultrasonography (TRUS) are useful in identifying prostate
Pathogenesis and Pathogenic abscess. During this time, prostate biopsy should not be
Microorganisms performed to avoid inducing septicemia.
Several natural defenses against infection for the prostate gland
are present, such as the production of antibacterial substances Differential Diagnosis
and the mechanical flushing of the prostatic urethra via voiding According to the complex clinical manifestations of acute
and ejaculation (Fair and Parrish, 1981). Nonetheless, bacteria prostatitis and the results of numerous auxiliary examinations,
still cause acute prostatitis by ascending urethral infection from the following diseases need to be identified: benign prostatic
the external urethral meatus, by flowing back from hypertrophy (BPH), CBP, CPPS, PCA, cystitis, acute
contaminated urine to the ejaculatory and prostate duct after pyelonephritis, epididymitis, and proctitis (Coker and
transurethral manipulations (e.g., catheterization and Dierfeldt, 2016) (Table 1).
cystoscopy), and by being implanted during a prostate biopsy
directly (Millan-Rodriguez et al., 2006; Kim et al., 2014; Coker
and Dierfeldt, 2016; Gill and Shoskes, 2016). Other pathogenic CBP (NIH CATEGORY II)
mechanisms include lymphatic invasion from the rectum and
hematogenous infection (Ramakrishnan and Salinas, 2010). CBP is defined as a prolonged urinary tract infection (UTI) that
The incidence and prevalence of ABP are not completely lasts 3 months or longer and recurrent UTIs with persistent
known. However, in general, the incidence rate of ABP in the source of urinary tract bacterial seeding (Krieger and Egan,
communities is three times higher than in hospitals (Etienne 1991). Most symptoms of CBP are similar to ABP but with
et al., 2008). According to the epidemiological survey of ABP, E. rare fever, which may recur within weeks or months. Digital
coli (accounting for 65%–80%) comprises the overwhelming prostate palpation in patients with CBP detects tenderness,
majority of the bacteria that cause this infection. Other causal softening (“bogginess”), firm induration, or nodularity (Lipsky
agents include Enterococcus, Pseudomonas aeruginosa, Proteus, et al., 2010). The prevalence of CBP is very low, with only 5%–
Klebsiella, Enterobacter, and Serratia (Yoon et al., 2012). 10% of all prostatitis cases suffering from this condition (Khan
Neisseria gonorrhoeae, Chlamydia trachomatis, certain fungi et al., 2017).

TABLE 1 | Differential Diagnosis of Acute Bacterial Prostatitis. microbe. Among sexually active male patients with CBP, chronic
Diagnosis Distinguishing characteris- Tests to rule out differential
mycoplasma infection generally leads to decreased fertility
tics diagnoses because of the impaired semen quality (including sperm
vitality, sperm total motility, and percentage of progressively
Benign Obstructive voiding symptoms; Inferior abdominal ultrasound
motile sperm) and a higher incidence of premature ejaculation
prostatic enlarged, nontender prostate; and uroflowmetry
hypertrophy negative urine culture
(Cai et al., 2014; Shang et al., 2014).
Chronic Recurrent UTIs with the same Urinalysis with each episode;
bacterial organism in prostatic DRE; Meares–Stamey four- Evaluation
prostatitis secretions at least 3 months glass test or PPMT For the diagnosis of CBP, completing quantitative sequential
Chronic Pain attributed to the prostate Urinalysis and midstream urine bacteriological localization cultures is necessary. The Meares–
pelvic pain with no demonstrable evidence culture; DRE Stamey four-glass test is considered as the gold standard for
syndrome of infection the diagnosis of CBP; in this test, first-voided urine (VB1),
Prostate Presence of constitutional PSA testing; MRI; TRUS; midstream urine (VB2), expressed prostatic secretions (EPS),
cancer symptoms; presence of prostate biopsy (only if prostate and post-prostate massage urine (VB3) are sampled (Lipsky
nodules on prostate cancer suspected based on
examination PSA and/or DRE results)
et al., 2010; Wagenlehner et al., 2013). Moreover, the
diagnosis is based on the substantially lower leukocyte and
Acute cystitis Irritative voiding symptoms; DRE; inferior abdominal
normal prostate examination ultrasound bacterial counts in VB1 and VB2 compared with VB3 and EPS
Acute Chills; fever; lumbago and Physical examination; urine
(Lipsky et al., 2010). Semen or ejaculate culture may increase
pyelonephritis backache; urine sediment sediment microscopic the diagnostic utility of the four-glass test, but is not sufficient
microscopic examination examination for diagnosis by it alone (Zegarra et al., 2008; Magri et al.,
revealed the leucocytes casts 2009; Wagenlehner et al., 2013). Considering the complexity
Epididymitis Tenderness to palpation on Physical examination; US of the four-glass test, a straightforward and more convenient
affected epididymis; irritative two-glass test is often performed in clinical practice for
voiding symptoms
diagnosis. The two-glass pre- and post-massage test
Proctitis Tenesmus; rectal bleeding; DRE; stool routine examination;
(PPMT), which requires clean catch urine specimen before
feeling of rectal fullness; proctoscopy
passage of mucus through the massage and a first-stream urine after, provides similar results
rectum and is a reasonable alternative for at least initial evaluation
UTI, urinary tract infection; PPMT, pre- and post-massage test; DRE, digital rectal
(Nickel et al., 2006). PSA levels are elevated in <20% of men
examination; PSA, prostate-specific antigen; MRI, magnetic resonance imaging; US, with this infection (Wise and Shteynshlyuger, 2008; Lipsky
ultrasonography. et al., 2010).
Pathogenesis and Pathogenic Differential Diagnosis

Several conditions that present with similar symptoms or results
Microorganisms
of examination must be differentiated from CBP (Rees et al.,
Distinct relationships are shown between ABP and CBP.
2015) (Table 2).
Epidemiology showed that nearly 10% of patients with ABP
may advance into CBP, and further 10% into CPPS (not
discussed in this article) (Yoon et al., 2012). The factors that
affected ABP evolve into CBP are diabetes, prior manipulation, GENERAL TREATMENT FOR ABP
not doing cystostomy, and urethral catheterization (Yoon et al.,
2012). Biofilm-producing bacteria acquiring lasting vitality is the Successful treatment of bacterial prostatitis is based on the
main reason for the characteristic persistence of infection despite selection of the appropriate therapeutic method (include
appropriate antibiotic therapy. The current study showed that operation and antibiotic), which depends on the severity of
biofilm formation may result in the increased ability of strains symptoms, bacterial flora, local antibiotic resistance patterns,
that cause acute prostatitis to persist in the prostatic secretory and the drug concentration in prostatic fluid (Figure 1).
system and lead to the recurrent UTIs characteristic of CBP (Soto
et al., 2007). Studies suggested that secretory inhibitor of platelet Classic Drug of Choice for Non-
microbicidal protein (SIPMP) production is associated with CBP Complicated ABP
although no consensus has been reached (Ivanov et al., 2008). Empiric antibiotic therapy may be selected as the initial
The existence of increased oxidative stress and damage may be treatment according to the local epidemiology of bacterial
closely associated with the long course of CBP (Lou et al., 2006). prostatitis to presume the mode of infection and the suspected
In the past, E. coli was considered the main cause of CBP, but pathogen before obtaining the results of blood and urine cultures
recent studies show that gram-positive bacteria, especially and drug sensitivity. During acute prostatic infection with
Enterococcus faecalis, have replaced E. coli and have been inflammation, antibiotics (except nitrofurantoin) easily
discovered as the causal agents (Bundrick et al., 2003; Cai penetrate the prostatic tissue to achieve the sufficient effective
et al., 2011; Heras-Canas et al., 2016). Furthermore, the bactericidal concentration (Nickel et al., 1995). The majority of
pathogen that causes recurrent episodes of UTI is the same ABP patients receive satisfactory therapeutic effect initially at

TABLE 2 | Differential Diagnosis of Chronic Bacterial Prostatitis. gonorrhoeae and C. trachomatis infection should receive a
Diagnosis Distinguishing characteristics Tests to rule out
standard treatment with cephalosporins and azithromycin or
differential diagnoses doxycycline, respectively (Skerk et al., 2004). The treatment of
ABP associated with genitourinary tuberculosis is recommended
Benign Obstructive voiding symptoms; Inferior abdominal ultrasound;
by the WHO with 2 months of daily isoniazid, rifampicin, and
prostatic enlarged, nontender prostate; uroflowmetry; urinalysis;
hypertrophy negative urine culture midstream urine culture; DRE
pyrazinamide with or without ethambutol or streptomycin and
Acute Acute episode of urinary tract Urine culture with each episode
immediately followed by four months of treatment with
bacterial symptoms, pelvic pain and (e.g., Meares–Stamey four- isoniazid and rifampicin two or three times a week. For
prostatitis systemic symptoms; history of glass test or PPMT); DRE complicated cases of genitourinary tuberculosis with HIV or
prostate manipulation and/or AIDS, antituberculosis therapy should be extended to 9–12
high-risk sexual behavior; past months (Cek et al., 2005). In addition, treatment for HIV
medical history (e.g., BPH,
urethral stricture, genitourinary
patients is based on initiation of highly active antiretroviral
infections, immunocompromised) therapy (HAART) to restore immunity (Brede and
Chronic Pain attributed to the prostate Urinalysis and midstream urine Shoskes, 2011).
pelvic pain with no demonstrable evidence culture ABP associated with transrectal prostate biopsy is becoming
syndrome of infection more common with an incidence rate in the range 0.6%–2.1%
Prostate Presence of constitutional PSA testing; MRI; TRUS; (Stoica et al., 2007; Miura et al., 2008; Shigehara et al., 2008;
cancer symptoms; presence of nodules prostate biopsy (only if prostate Brede and Shoskes, 2011). Also, fluoroquinolone-resistant strains
on prostate examination cancer suspected based on
of E. coli were observed in most cases (Stoica et al., 2007; Miura
PSA and/or DRE results)
et al., 2008; Shigehara et al., 2008). A retrospective study by
Chronic Tenderness and presence of Physical examination; US
epididymitis nodules on affected epididymis
Shigehara et al. showed that a risk factor of fluoroquinolone-
palpation; discomfort in the resistant E. coli may have been caused by the use of levofloxacin
scrotum and groin at least 3 for prophylactic treatment, and to avoid this strain from
months generating, patients should receive levofloxacin for a short
Prostatic Systemic symptoms of DRE; TRUS; X-ray examination; period before biopsy (Shigehara et al., 2008). Moreover, it is
tuberculosis tuberculosis; past history of prostatic fluid and semen recommended for patients with acute prostatitis to receive
tuberculosis; irregular culture; prostate biopsy if
enlargement of the prostate and necessary
treatment with cephalosporin or carbapenem after prostate
seminal vesicle and with biopsy (Shigehara et al., 2008). A randomized controlled trial
tuberculous nodules to palpation conducted among 100 volunteers who had an indication for
BPH, benign prostatic hypertrophy; PPMT, pre- and post-massage test; DRE, digital
prostate biopsy determined the efficacy of rectum sterilization
rectal examination; PSA, prostate-specific antigen; MRI, magnetic resonance imaging; before TRUS-guided prostate biopsy to decrease bacteremia rate
US, ultrasonography; TRUS, transrectal ultrasonography. and sepsis complications (Kanjanawongdeengam et al., 2009).
If acute prostatitis resolves slowly or fail to respond within 36 h
outpatient service with less than 6% requiring hospitalization with continued systemic symptoms, and a fluctuant mass in the
(Millan-Rodriguez et al., 2006). For non-severe patients without prostate is observed, we should consider the presence of prostatic
systemically ill and urinary retention, oral fluoroquinolone, abscess. Prostatic abscess, a serious complication of ABP, is
trimethoprim-sulfamethoxazole, broad-spectrum penicillin particularly susceptible in patients who are immunocompromised,
derivative, or third-generation cephalosporin is usually the first diabetic, with cirrhosis or renal impairment, and who are managed
choice for empirical therapy as an outpatient. The quinolones with an indwelling urethral catheter or clean intermittent self-
reach three to four times higher intraprostatic concentrations catheterization (Aravantinos et al., 2008; Benway and Moon,
than b-lactam antibiotics (Goto et al., 1998). 2008). Using CT, MRI, or TRUS to diagnosis prostate abscess
is helpful. Treatment plans should be formulated according to
Classic Drug Choice for Complicated ABP the size of prostate abscess. Generally, drainage or conservative
An acutely ill patient with a clinical picture of sepsis or a systemic treatment is effective and feasible. Prostate abscesses less than 1
inflammatory response syndrome must be accepted for cm in diameter could be treated conservatively with oral drug.
hospitalization with parenteral antibiotics that broadly cover Although no standard of care exists, quinolones (such as
fluoroquinolone plus an aminoglycoside or a combination of the ciprofloxacin) are recommended for outpatient and a third-
above with a penicillin or second/third-generation cephalosporin generation cephalosporin, aztreonam, or the combination of an
(Brede and Shoskes, 2011). Once the clinical condition of the aminoglycoside with ampicillin for those are debilitated or
patient is stable without fever and urinary retention, oral antibiotic immunocompromised with atypical or-resistant organisms
therapy should replace intravenous medication for 2–4 weeks, infected (Ackerman et al., 2018). Whereas, larger ones require
based on the results of blood and urine culture and drug single aspiration or continuous drainage (Chou et al., 2004).
sensitivity. It is necessary to plan repeat urine culture during Transrectal ultrasound-guided aspiration of the abscess is the
and 1 week after therapy to ensure bacterial eradication. first-line of therapy for patient with abscess larger than 2 cm with
Sexually active men younger than 35 years old and men older severe LUTS and/or leukocytosis (Vyas et al., 2013). If the
than 35 years old with high-risk sexual behavior suspected of N. abscess is large and with multiloculated infections,

FIGURE 1 | Treatment algorithm for acute bacterial prostatitis.
transurethral unroofing of prostate abscess might be more Mechanism of Antimicrobial Therapy for
appropriate (Goyal et al., 2013). Besides, transurethral CBP
unroofing with resection of the prostate is fit for patient with Different from ABP, the therapeutic strategy for CBP is to select
BPH (prostate sizes of ≥80 g), recurrent or residual abscesses and antibiotics with strong ability to permeate prostatic tissue and
persistent lower urinary tract symptoms (LUTS) (Goyal advantageous pharmacokinetics. Drug penetration is supposedly
et al., 2013). associated with the passive transport mechanism that constitutes
diffusion and concentration (Wagenlehner et al., 2005).
Therapeutic agents with high pKa, low protein binding, a low
GENERAL TREATMENT FOR CBP degree of ionization (biological membranes do not allow the
passage of charged substances), high lipid solubility, and small
Treating CBP is challenging, because only few oral antibiotics water-soluble molecules (small water-soluble molecules can
could penetrate the prostate and achieve sufficient effective cross biological membranes as part of free water diffusion) are
bactericidal concentration at the field of infection (Lipsky recommended to treat CBP, as these factors facilitate the drug’s
et al., 2010; Karaiskos et al., 2019). A reproducible rat model of passage through the prostatic epithelium and penetrate into the
CBP has shown that the acinar and interstitial spaces are the prostatic infective tissue. The presence of a pH gradient across a
most susceptible part of infection (Nickel et al., 1991). Thus, biological membrane introduces the phenomenon of ion
pathogens at prostatic secretion and tissues must be exposed to a trapping. In a stable system, the uncharged fraction of a lipid-
sufficiently high concentration of antibiotics for effective therapy soluble drug equilibrates on the two sides of the membrane, but
that would inhibit bacterial growth or eradicate pathogens from the charged fraction is greater on one side or the other,
the site of infection (Wagenlehner et al., 2005). In addition, with depending on the pH values. The greatest drug concentration
the emergence of multidrug resistance (MDR) and/or ESBLs- (sum of charged and uncharged fractions) is on the side with the
producing bacteria, biofilm-producing bacteria and the shift in higher degree of ionization (Wagenlehner et al., 2005). The pH
bacterial etiology, the therapeutic schemes of CBP become value of human prostatic secretion of normal men is alkaline,
complex and tricky (Figure 2). and the pH of prostatic secretion from men with prostatic

FIGURE 2 | Treatment algorithm for chromic bacterial prostatitis. (MDR, multi-drug resistance; ESBLs, extended spectrum b-lactamases). *Combination therapy:
Plant extracts combinate with antibiotics, antibiotics combinate with antibiotics and other drug combinate with antibiotics.
infection is markedly increased (mean pH 8.34) (Naber and been internationally considered as the cornerstone for the
Sorgel, 2003). Thus, the concentrations of trimethoprim, a weak treatment of CBP because of their broad-spectrum
base with a pKa of 7.4, may be inadequate in an alkaline milieu, antimicrobial properties and advantageous pharmacokinetics in
such as in infected prostatic secretion and seminal fluid. The prostatic tissue. The overall rate of clinical and microbiological
fluoroquinolones in clinical use are amphoteric (neither pure responses in prostatitis with CBP is 70%–90% at the end of
acids nor bases, but have characteristics of both) or zwitterionic therapy with oral fluoroquinolones, but only 60% after half a year
drugs with two ionizing groups (positively and negatively (Khan et al., 2017). In general, for E. coli and other family
charged); thus, they have two pKa values (Sorgel et al., 2001). members, such as Enterobacteriaceae without antibiotic
The amount of charged drug is minimal (isoelectric point) at a resistance, bacterial eradication rate of fluoroquinolones is
pH value between the two pKa values, whereas it is maximal at satisfactory in the case of CBP (Khan et al., 2017). Some
higher and lower pH values. Moreover, drugs are transferred to studies showed that levofloxacin 500 mg once daily per os for
the side with a higher degree of ionization. Hence, some 28 days and ciprofloxacin 500 mg twice daily for 28 days are both
fluoroquinolones with an isoelectric point close to plasma pH clinically and microbiologically effective in the treatment of CBP
may be concentrated in fluids with a pH value above and below caused by susceptible pathogens without severe complications
plasma pH, such as the alkaline prostatic secretion from men (Bundrick et al., 2003; Naber et al., 2008). Kurzer, E. et al.
with bacterial prostatitis and seminal fluid (Naber et al., 1993; established a model that compared 90 days of double strength
Naber et al., 2001). Therefore, the concentration of some trimethoprim-sulfamethoxazole with 14, 28, and 60 days of
fluoroquinolones in the alkaline seminal fluid may even exceed ciprofloxacin at 500 mg, which indicated that ciprofloxacin 500
those in the plasma. In addition, macrolides also easily penetrate mg twice daily for 28 days is the most cost-effective treatment for
into prostatic and seminal fluids. the disease (Kurzer and Kaplan, 2002). To investigate the safety
and efficacy of levofloxacin compared with ciprofloxacin in
Classic Antibiotic Choice for CBP Chinese patients with CBP, a trial comparing the effects of oral
A high proportion of E. faecalis (gram-positive bacteria) and levofloxacin (500 mg q.d.) and ciprofloxacin (500 mg b.i.d.)
most E. coli (gram-negative bacteria) have been isolated in administered for 4 weeks on 408 male patients showed that
prostatic fluid and urine of patients with CBP in a series of levofloxacin have some advantages over ciprofloxacin in terms of
studies, which emphasize the necessity of selecting antibacterial the bacterial clearance rate, clinical efficacy, adverse events, and
agents with broad-spectrum activity. Fluoroquinolones have disease recurrence (Zhang et al., 2012). A study investigating the

penetration of moxifloxacin into prostatic tissue in patients with broad-spectrum bactericidal activity, which covers common
benign prostatic hyperplasia showed that the concentrations of pathogens associated with prostatitis and advantageous
moxifloxacin in the serum and prostatic tissue were well above pharmacokinetics in prostatic tissue (Lipsky et al., 2010;
the minimal inhibitory concentration (MIC) values of most Videcnik et al., 2015). Oral fluoroquinolones have become a
important prostatic pathogens after 400 mg of moxifloxacin major contributor to use and resistance of antibiotics because of
intravenous infusion. The high tissue/serum ratio and the the high incidence rate of UTIs (Costelloe et al., 2010;
extended antibacterial spectrum imply that the active Zalmanovici et al., 2010). Although 10% of men diagnosed
concentration in the prostate may translate into increased with prostatitis have bacterial infection, approximately 1/2 are
efficacy in the treatment of CBP (Wagenlehner et al., 2006). treated with antibiotic therapy. The consequence of resistance
Moreover, an evidence of the effectiveness of moxifloxacin in the due to widespread use has led to therapeutic failures with
established pharmacokinetic (PK) model by K, Hurtado F et al., antibiotics. Fluoroquinolone resistance among clinical isolates
in which moxifloxacin with enhanced tissue penetration and of E. coli has been reported since 2002. A steep increase in
high area under the concentration–time curve in tissue urinary and prostatic infections due to MDR gram-negative
(AUCtissue)/MIC ratios was suggested as a better alternative to Enterobacteriaceae globally, even in the community, and the
levofloxacin for the treatment of CBP when the pathogenic agent prevalence of ESBL-producing bacteria render invalidity to
is resistant to levofloxacin (Hurtado et al., 2014). Unfortunately, fluoroquinolones and affect the choice of treatment options (de
the recurrence rate of CBP ranged from 25% to 50%, even with la Rosette et al., 1993; Zowawi et al., 2015; Zhanel et al., 2018).
the appropriate type and duration of treatment (Weidner et al., Fluoroquinolones resistance in urinary E. coli is reportedly as
1999; Bundrick et al., 2003). If the source of prostatic infection high as 70%, and approximately 60% of strains produce ESBLs
cannot be eliminated, the long-term use of low-dose oral simultaneously in many Asian countries, including China, India,
antibiotics, such as trimethoprim, for inhibitory treatment can and Vietnam (Zowawi et al., 2015). The international research
reduce symptom recurrence, but future studies should be community has deemed these as the greatest and most urgent
designed to demonstrate this viewpoint (Perletti et al., 2013). universal risk (Laxminarayan et al., 2016).
MDR is defined as non-susceptibility to at least one agent in
Other Choice for CBP three or more antimicrobial categories (Magiorakos et al., 2012).
Non-steroidal anti-inflammatory drugs significantly reduce Recent studies indicate that the increase of resistance to
prostate-related pain (Pontari, 2002). In addition, the use of fluoroquinolone is due to the emergence and proliferation of a
alpha-1-adrenergic antagonists contributes to prostate-related MDR subclone of sequence type 131 (ST131). ST131 also
LUTS (Nickel and Touma, 2012). Experiments suggest that contributes to the transmission of ESBL-producing E. coli that
finasteride may prevent CBP progression, although no mainly carry CTX-M-14 and CTXM-15 (Karlowsky et al., 2011;
consensus was reached on its mechanism (Lee et al., 2011). Denisuik et al., 2013; Karlowsky et al., 2014).
The existence of prostate calculi or calcification is associated with In the 1980s, the emergence of ESBLs in Enterobacteriaceae
the persistence of prostatic infection because of biofilm infection was witnessed globally (Zowawi et al., 2015). ESBLs can
and is likely to relapse after antibacterial treatment (Zhao et al., hydrolyze third-generation cephalosporins, such as ceftriaxone
2012; Bartoletti et al., 2014). Therefore, if antibacterial treatment or ceftazidime, and aztreonam (Paterson and Bonomo, 2005).
for the abovementioned situations failed, then the surgical Typically, ESBLs are derived from genes for TEM-1, TEM-2, or
removal of these factors may have positive implications for SHV-1 by mutations that alter the amino acid configuration
prostatitis treatment. around the active site of these b-lactamases (Paterson and
Acute urinary retention may occur in approximately 10% Bonomo, 2005). Presently, ESBL-producing E. coli and
patients with ABP, including acute episodes of CBP. Urinary Klebsiella pneumoniae are prevalent in medical institutions,
tract decompression is the key to remove infection and alleviate even in the community (Doi et al., 2013). The CTX-M-type
pain. The best intervention approach is intermittent or short- ESBL is the most common ESBL associated with uropathogenic
term indwelling urethral catheter to relieve obstruction, but this Enterobacteriaceae that may lead to global spread. ESBL-
may increase the risk of ABP’s progression to CBP (Yoon et al., producing E. coli emerging in Europe and North America
2012). For patients who cannot tolerate catheters, suprapubic accounts for approximately 97% producing CTX-M-type ESBL
cystostomy may be an option. Alpha-blocker treatment is also (Hoban et al., 2012). Considering the combination with ESBL
recommended, but the clinical evidence for this approach is weak genes and other antimicrobial resistance genes on plasmids
(Nickel et al., 2006). (mobile genetic elements that spread easily between bacteria),
strains obtain MDR.
If the empirical treatment is ineffective, then the treatment
NEW INTERNATIONAL CHALLENGES IN strategy should be adjusted based on the results of bacterial
TREATMENT culture and drug sensitivity. Third-generation cephalosporin
(such as ceftazidime and ceftriaxone) and even carbapenem
MDR and/or ESBLs-Producing Bacteria (such as imipenem or ertapenem) are usually alternative
For 25 years, oral fluoroquinolones have been considered as the antibiotics for fluoroquinolone resistance (Shigehara et al.,
cornerstone of treatment for bacterial prostatitis because of their 2008). The availability of empirical treatment of combination

with abroad-spectrum b-lactam drug (either a penicillin or a 0.18 mg/L; ciprofloxacin, 1–4 mg/L; levofloxacin, 1.42 mg/L,
cephalosporin) and an aminoglycoside for patients, who are normalized to a 400 mg oral dose of moxifloxacin) are often
severely ill or who have recently received antibiotic therapy, below or sometimes just above the MICs for susceptible E.
have been confirmed. Carbapenems resistant to hydrolysis by faecalis (Hallgren et al., 2001; Magri et al., 2011a). This
ESBLs are the most frequently recommended antibiotics for the phenomenon of changing disease epidemiology explains the
treatment of MDR bacteria (Paterson and Bonomo, 2005). relatively low eradication rates of E. faecalis (50%–70% with
However, the deeply increased expenditure of carbapenems fluoroquinolones) compared with E. coli (between 70% and 90%)
over the past two decades around the world, particularly in (Magri et al., 2011a). This shift in bacterial etiology has profound
developing countries, indicates the rapidly developing influence on the therapy of CBP. Unfortunately, as for oral
phenomenon of carbapenem resistance in key gram-negative agents, rare studies have reported so far the successful outcome
pathogens (Rogers et al., 2014; Van Boeckel et al., 2014). of linezolid or moxifloxacin therapy which perhaps the only
Carbapenem resistance tends to emerge in areas where ESBL available fluoroquinolone that may attain prostatic secretions
prevalence is high, driven by selection pressure from carbapenem concentrations 10-fold above the MIC for E. faecalis (Hallgren
use, and subsequently spread through international travel and et al., 2001; Wagenlehner et al., 2008). Moreover, the increase in
globalization. The production of carbapenemases, such as KPC- resistance of Enterococcus strains secreting pathogenicity factors
type (K. pneumoniae carbapenemase), NDM-type (New Delhi is more alarming, due to which chronic inflammation is
metallo-b-lactamase), and OXA-48-type enzymes, is the maintained in the genitourinary system (Neimark et al., 2010;
significant mechanism underlying carbapenem resistance Stamatiou and Pierris, 2017).
among Enterobacteriaceae (Poirel et al., 2012; Munoz-Price The evaluation of microbiological characteristic for each CBP
et al., 2013; Wailan and Paterson, 2014). High-level expression patients to perform a correct, appropriate, and personalized
of ESBL or AmpC b-lactamases in conjunction with outer- treatment schedule is essential (Cai et al., 2011). Therefore,
membrane porin changes and increased activity of efflux Magri, V et al. proposed to dismiss empirical therapy to avoid
pumps are other mechanisms that result in carbapenem catastrophic consequences in terms of chemoresistance and poor
resistance (Peleg and Hooper, 2010). The Centers for Disease clinical practice (Magri et al., 2011a).
Control and Prevention (CDC) have defined carbapenem-
resistant Enterobacteriaceae as an urgent antibiotic resistance Bacterial Biofilm
threat (Centers for Disease Control and Prevention, 2013). In In addition to the production of MDR gram-negative E. coli and
addition, the infection of carbapenem-resistant Enterobacteriaceae the transformation of dominant pathogenic bacteria, the
leads to the death of approximately 50% of patients. Clinicians formation of biofilm is also an important factor that affects the
should consider local drug resistance patterns in selecting treatment of bacterial prostatitis according to urologists. Biofilms
antibiotics, especially with the emergence of ESBL-producing are currently defined as structured bacterial communities
strains in complicated UTIs, and should adjust therapy based on embedded in a self-produced exopolysaccharide matrix
culture results. adherent on any abiotic or biological surface (Costerton et al.,
1995). Before pathogenic microorganism form biofilms,
The Shift in Bacterial Etiology antibiotics are the most effective treatment for ABP when
As early as 2003, Bundrick et al, have described that E. faecalis bacteria are in the free-floating state. However, once biofilms
and E. coli were the most common isolates; the former was the are formed, the effectivity rate of antibiotic treatment is
major infection among cohorts of patients with CBP (Bundrick immensely decreased. Biofilms can protect bacteria from the
et al., 2003). An epidemiological investigation of the killing activity of host-defense mechanisms and antibiotics by
uropathogens among 6221 Italian patients with CBP from producing dense extracellular matrix and creating an
January 1997 to December 2008, showed that incidence of environment in which bacteria cooperate and interact, as well
gram-positive was higher than gram-negative bacteria, and E. as from the clearing out effect of the hydrodynamic force
faecalis prevalence increased within 2006–2008 (Cai et al., 2011). (Andrea et al., 2003). Hemolysin and the expression of type 1
Moreover, E. faecalis prevalence has also been reported in North fimbriae are related to biofilm production, which causes acute
America (Bundrick et al., 2003; Nickel and Xiang, 2008) not just prostatitis (Soto et al., 2007). Furthermore, biofilm-producing
to Italy. Recently, a clinical and microbiological survey of 332 bacteria acquiring lasting vitality are the main reason for the
cases of CBP showed that E. faecalis was the main etiologic agent characteristic persistence of infection despite appropriate
(37.7%), followed by E. coli (22.2%) among patients diagnosed antibiotic therapy (Soto et al., 2007).
microbiologically with CBP (Heras-Canas et al., 2016). These The current study showed that biofilm formation may result
results indicate that the predominant etiologic determinant of in the increased ability of strains that cause acute prostatitis to
CBP is gradually transferring to E. faecalis, which belongs to persist in the prostatic secretory system and lead to the recurrent
gram-positive microorganisms. Wagenlehner indicated that the UTIs characteristic of CBP (Soto et al., 2007). Inside the biofilms,
improved clinical use of fluoroquinolones for CBP patients a small fraction of cells are dormant bacteria that are almost
increased the trend of gram-positive infections (Wagenlehner immune to the effects of antibiotics, and these dormant inert
et al., 2008). bacteria could lead to recurrences (Kanamaru et al., 2006; Soto
The concentrations of most fluoroquinolones in the serum et al., 2007; Mazzoli, 2010). Therefore, there are significant
and prostatic tissue (eg, norfloxacin, 0.08 mg/L; ciprofloxacin, negative influences on the clinical efficacy for antibiotic

therapy to biofilm-producing bacteria. The improvement in faecalis reported lately by a systemic review was 95%, 83.8%, and
clinical symptoms after treatment seem more associated with 96.8%, respectively (Fan et al., 2018). Clinically, a case report of
the decrease in bacterial biofilm production than the negative the successful administration of oral fosfomycin on patients with
microbiological tests (Bartoletti et al., 2014). However, the CBP who were infected by a complicated vancomycin-resistant
survival of biofilm-producing bacteria may have caused the Enterococci demonstrated that fosfomycin is available (Shrestha
persistence of symptoms in patients with CBP despite apparent et al., 2000).
negative microbiological tests. Fosfomycin belongs to a broad-spectrum antimicrobial class
The etiology theoretically means that the whole range of with bactericidal activity against gram-negative and gram-
bacterial species that cause prostatitis are able to form biofilms, positive bacteria and is not relevant to any clinically approved
including E. coli, Staphylococcus, Enterococcus, and Ureaplasma antibiotics on the structure (Sastry and Doi, 2016). The unique
spp (Garcia-Castillo et al., 2008). Soto et al. suggested that biofilm bactericidal action of fosfomycin involves obstructing the
formation in prostate tissue by persistent and antibiotic-resistant synthesis of bacterial cell wall by inhibiting pyruvyl transferase,
E. coli strains causes the relapse of CBP (Soto et al., 2007). The a cytoplasmic enzyme that catalyzes the first step of
majority of the E. coli, E. faecalis, and Staphylococcus (85% of all peptidoglycan biosynthesis (Cunha et al., 2015; Fan et al.,
strains) are strong or medium producers around the world. Only 2018). A study involving a rat model has shown the effects of
6% of E. coli strains and approximately 10% of all other gram- reduction of bacterial reproduction, inhibition of inflammation
negative strains are not biofilm producers (Bartoletti et al., 2014). (with significant lower IL-6, IL-8, anti-TNF-a, and PSA levels in
Strong microorganisms that form microbial biofilm structures are the prostate tissue), and improvement of prostatic tissue injury in
often not eradicated by antibiotic treatment. Moreover, the the treatment of bacterial prostatitis using fosfomycin (Fan et al.,
relevance between bacterial biofilms and antibiotic-resistant E. 2018). The serum half-life (t1/2) of fosfomycin is 5.7 h,
coli strains that cause the relapse of symptoms has been confirmed bioavailability is approximately 37%, and excretion rate
(Cai et al., 2018). through the kidneys is 60%. Fosfomycin with a large volume of
Biofilm production increases the rate of incidence, distribution (Vd of ~2 L/kg) indicates extensive tissue/cellular
recurrence, and drug resistance of bacterial prostatitis and penetration (Cunha et al., 2015). The concentration of
threatens the ability of urologists to treat bacterial prostatitis. fosfomycin can achieve therapeutic concentration (prostate
New therapeutic strategies should be added to eradicate bacterial levels >4 µg/g) in infected prostate and is higher than in
biofilm formation to improve existing treatment of patients with healthy tissue (Gardiner et al., 2014; Karaiskos et al., 2019).
bacterial prostatitis. Soto et al. thought the detection of biofilm- The pharmacological properties of fosfomycin (including the
producing bacteria could be used to determine whether patients high lipid solubility, small molecular size, and low protein
should require prolonged- or short-therapeutic regimens (Soto binding) are conducive to the penetration of the parenchyma
et al., 2007). Wu et al. suggested that the inhibition of bacterial of the lipid-rich prostate (Lipsky et al., 2010; Cunha et al., 2015;
attachment to a urothelial surface could be a crucial procedure to Zhanel et al., 2016). Based on the present studies, fosfomycin can
avoid biofilm formation (Wu et al., 1996). Future studies should effectively prevent the relapse of UTIs in patients with prior
be designed to explore whether effective eradication of the history of urinary colonization and infections caused by
bacterial biofilm could be associated with a good medium- and complicated pathogens, such as ESBL-producing E. coli and
long-term clinical outcome of treatment. MDR bacteria (Almeida et al., 2019). In addition, fosfomycin
also has a significant effect on biofilm-producing bacteria,
including E. coli (Corvec et al., 2013).
LATEST THERAPEUTIC STRATEGY To determine the safety of the treatment with fosfomycin, a
prospective observational study was conducted in 44 men with
The Revival of Fosfomycin CBP; results showed that oral fosfomycin was well tolerated with
Considering that the evolving changes in resistance rates for minor side effects, even when the treatment was prolonged for 90
fluoroquinolones have a serious impact on treatment, alternative days (Karaiskos et al., 2019). Moreover, the study indicated that
antibiotic therapies are urgently needed. Studies have the only adverse effect was diarrhea in 18% of the participants (8
demonstrated fosfomycin has a strong killing effect in vitro of 44). However, this effect subsided when dose intervals and/or
against antimicrobial-resistant E. coli (including ESBL- modificatory dietary were lengthened during the course of
producing, AmpC-producing, and MDR isolates). This new fosfomycin administration (Karaiskos et al., 2019).
discovery inspires the treatment of refractory bacterial Oral fosfomycin, as an alternative therapeutic option in the
prostatitis (Michalopoulos et al., 2011; Gardiner et al., 2014; case of bacterial resistance to classic antibiotic or poor tolerability
Falagas and Rafailidis, 2015). Fosfomycin, an old drug used to the first-line agent, is recommended at least 6 weeks up to 12
before for therapy of females uncomplicated cystitis and weeks (Karaiskos et al., 2019). The present evidence supports the
transrectal prostate biopsy prophylaxis, has been recently idea that the most effective dose interval is 48 h. An oral
rediscovered as a treatment for MDR infections with an fosfomycin dosage of 3g.q24h for the first week followed by
effective rate >90% in lowering UTIs (Pullukcu et al., 2007; 3g.q48h for the remaining duration appears to have the highest
Senol et al., 2010). In addition, fosfomycin-susceptibility rate of clinical cure rates that also minimizes gastrointestinal adverse
ESBL-producing E. coli, ESBL-producing K. pneumoniae, and E. effects (Zhanel et al., 2018). High-dose fosfomycin (> 3 g per

dose) has not demonstrated enhanced clinical efficacy compared population of a few to over 1000 viral particles, depending on
with 3 g doses of treatment (Cunha et al., 2015). Appropriate environmental factors. Environmental stressors on the bacterial
adjustment of fosfomycin dosage or frequency when adverse host can induce the lysogenic phage from the latent prophage
gastrointestinal effects occur would easily solve the problem. The form, thereby triggering a transition to the lytic cycle. The latter
presence of prostate stones and biofilm-producing bacteria becomes active and hydrolyzes the peptidoglycan cell wall,
contributes to the persistence of infection and easily leads to thereby releasing novel phage to reinitiate the lytic cycle
recurrence following antimicrobial therapy. Thus, the (Weinbauer, 2004). In contrast to lytic phages, lysogenic
prolongation of treatment duration to a median period of 12 phages integrate their genetic material into the bacterial
weeks with single oral dose of 3 g of fosfomycin has been chromosome in the form of an endogenous prophage. The
suggested to apply without significant adverse event to the ability of the phages to kill the bacterial cells forms the basis of
aforementioned cases (Zhao et al., 2012; Bartoletti et al., 2014). the idea of using phages as therapeutic agents. In addition, lytic
In addition, the prostatic calcifications are suggested to be phages are compiled into preparations called “phage cocktails,”
removed by transurethral resection of the prostate (Cunha which consist of multiple phages proven to have in vitro efficacy
et al., 2015). Rhodes et al. suggested that 3 g of oral fosfomycin against the target pathogen (Lin et al., 2017).
should be administered 1–4 h prior to prostate biopsy to prevent Given the absolute difference between phages and those of all
postoperative infection (Rhodes et al., 2015). A case of persistent antibiotics in terms of mechanism of action, phages are effective
ESBL-positive E. coli CBP refractory to antibiotic therapy against multidrug-resistant bacteria (Hanlon, 2007). Phages can
showed that the combination with doxycycline and fosfomycin target pathogens without notably affecting the normal flora of
might have synergistic effect, in which the antibacterial activity of bacteria because of the narrower antibacterial spectrum of
one antibiotic enhances the intracellular transport and/or phages than antibiotics (Chibani-Chennoufi et al., 2004).
antimicrobial activity of the other. Thus, the ability of prostate Similar to antibiotics, resistance mechanisms can be evolved by
penetration and/or penetrating into his infected prostate bacteria to resist the killing infection of lytic phages. However,
calcifications/biofilm increased (Cunha et al., 2015). the phage can also enable opposite mechanisms to avoid,
circumvent, or subvert host limitations by recognizing new or
Phage Therapy in Bacterial Prostatitis altered receptors and anti-CRISPR genes (Hyman and Abedon,
Phages, bacterial viruses, were used in the treatment of bacterial 2010; Labrie et al., 2010). CRISPR/Cas is programmed to disrupt
infections because they show characteristics of infecting and lysing antibiotic resistance genes and destroy antibiotic resistance
bacteria that have been discovered almost a century ago. Although plasmids (Yosef et al., 2015). Innovations in the gene editing
they were abandoned by the western world after the discovery of tool CRISPR/Cas have created novel opportunities for PT.
antibiotics, the phenomenon of the global effective decline in Interestingly, Levin et al. found that the bacterial mutant
antibiotic therapy has forced scientists to look for alternative generation that resist phage might be accompanied by the
strategies for prophylaxis and control of bacterial infection. decline of bacterial virulence (Levin and Bull, 2004).
Phage therapy (PT) may be one of the most popular choices Direct antibacterial action and immunomodulating effects
nowadays. Several major advantages, such as host-specificity, self- mediated by the phages themselves and by bacterial antigens
amplification, biofilm degradation, and low toxicity to humans, are present in the phage lysates that are used for PT (Letkiewicz
are attributed to PT in comparison with antibiotics therapy et al., 2010b). Moreover, all forms of prostatitis, especially CBP,
(Donlan, 2009; Bourdin et al., 2014). Moreover, phages are able may benefit from the immunomodulating effects of phages.
to selectively infect and kill bacterial cells, even those that have Phages downregulate the expressions of TLR4 and MHC class,
acquired resistance to antibiotics, such as vancomycin-resistant both of which are implicated in the immunopathology of
Enterococcus faecium (Biswas et al., 2002). prostatitis (Van Belleghem et al., 2017). Experiments of
Phages are simple but genetically diverse, non-living Miedzybrodzki et al. showed that neutrophils that were
biological entities that mostly consist of double-stranded (ds) stimulated both by live bacteria and by their endotoxins could
DNA, single-stranded (ss)DNA, ssRNA, or dsRNA (Hatfull, induce the inhibition of the formation of reactive oxygen species
2008). Phages are naturally occurring bacterial parasites that in PT, even independent of the phages’ capability to hydrolyze
cannot generate independently, that is, they are non-living. Thus, the bacterial-peptidoglycan cell wall (Miedzybrodzki et al., 2008).
these parasites depend on the bacterial host for survival. Phage This activity may play an important role in reducing the
life cycles can be divided into lytic and lysogenic period, besides oxidative stress that accompanies the chronic-inflammatory
they can replicate in the host bacteria at both period (Hanlon, process in the CBP (Zhou et al., 2006). Result of a significant
2007). Conventional PT relies on strictly lytic phages that decline in C-reactive protein level in patients treated with phage
obligately kill the bacterial host. Phages typically bind to preparations suggested the anti-inflammatory properties
specific receptors on the surface of bacterial cell, inject their (Miedzybrodzki et al., 2009).
genetic material into the host cell, and then either integrate this Published experimental finding of Nishikawa et al.
material into the bacterial genome to reproduce vertically from demonstrated the large potential of phage (T-even-related
mother to daughter cell or hijack the bacterial replication phage may be the suitable candidate) in the treatment of E.
machinery to produce the next generation of phage progeny. coli-induced UTIs (Nishikawa et al., 2008). A cohort of 27
Upon reaching a critical mass, phage progeny can have a patients with CBP received PT, Letkiewicz et al. reported that a

significant decrease in the EPS leukocyte count, conspicuous Therapeutic phages are generally regarded as safe (Bruttin
reduction of the prostate volume, and an increase in Qmax were and Brussow, 2005; McCallin et al., 2013). Although not enough
noted. As confirmed by two consecutive EPS cultures, evidence shows that these phages can cause significant adverse
eradication of pathogen was observed in 13 patients, without effects or serious harm in mammalian cells, the possibility of
significant side effects. All these results indicated that PT could bacteriophage-mediated transfer of genes that are involved in
be efficient in patients with CBP (Letkiewicz et al., 2010a). The bacterial pathogenicity should be a focus of research (Gorski
same author also reported a case of PT-eradicating E. faecalis in et al., 2009). Generally, only the obligately lytic phages and not
CBP (Letkiewicz et al., 2009). Encouraging results were obtained lysogenic phages are considered as suitable substrates for the
by the application of PT to bacterial eradication, such as therapeutic phage preparations, because the latter cannot destroy
improvement in NIH-chronic prostatitis symptom index the bacterial cell immediately (Letkiewicz et al., 2010b). As for
(NIH-CPSI) and lack of early disease recurrence. immunocompromised patients with diseases such as AIDS, the
Bacterial biofilm polysaccharide normally protects the bacteria immunological response to phage may be indicative of the
against the majority of antibiotics because of its resistance to potential for an adverse reaction, which could hypothetically
antimicrobial treatment and removal by the host immune system. worsen a patient’s condition. Currently, there is no consensus on
However, phages specific to Enterobacter agglomerans can this possibility (Borysowski and Gorski, 2008). A recent study
produce the specific polysaccharide depolymerases that may be indicated that a serious implication known as “leaky gut” may be
able to degrade the extracellular polysaccharide matrix of biofilms linked with the potential of PT to disrupt normal intestinal
(Hughes et al., 1998). Some studies showed that phage T4 is barrier function in patients with several disorders such as
capable of infecting and multiplying within biofilm-producing E. Crohn’s disease, inflammatory bowel disease, and type 1
coli cells and then disrupting the morphology of the biofilm. Thus, diabetes (Tetz and Tetz, 2016).
bacterial cells are not protected from the extracellular matrix of One should be aware that the general use of phages as an
the E. coli biofilms (Doolittle et al., 1995). In addition, T4-like alternative to antibiotics will be possible when their efficiency and
phages (the majority of therapeutic phages belong to this family) safety have been verified in large-scale and controlled clinical trials.
and some antibiotics such as b-lactams, quinolones, and
mitomycin C show a phenomenon of related effect that is Preventive Action in Plant Extracts
named phage-antibiotic synergy (Comeau et al., 2007). Antibiotics (levofloxacin and other fluoroquinolones) have been
Bacteriophage that express a biofilm-degrading enzyme during recommended to be the preferred treatment for bacterial
infection was engineered by Lu and Collins to attack the bacterial prostatitis for years. However, the eradication rates of E. faecalis
cells in the biofilm and to attack simultaneously the biofilm and E. coli treated with fluoroquinolones vary greatly, ranging
matrix composed by extracellular polymeric substances, thereby between 50%–70% and 70%–90%, respectively (Magri et al., 2011a;
demonstrating that it is also feasible to construct genetically Magri et al., 2019). Therefore, much interest has surrounded non-
engineered enzymatic phages with greater efficacy against antimicrobial-based approaches. Plant extracts that have long been
biofilm (Lu and Collins, 2007). used for prevention and treatment of urinary tract disorders in
Recent data indicated that phages are capable of penetrating traditional medicine are becoming increasingly popular with
the epithelial cell layers and spreading throughout the cell scholars, especially in this era of antibiotics resistance.
structure and subsequently the body, including the blood, Given that the anti-inflammatory and antibiotic properties of
lymph, organs, and even the brain (Nguyen et al., 2017). cranberry prevent E. coli from adhering to urothelial cells,
Furthermore, Gorski et al. developed a phage bank that was acidifying the urine, and impair colonization and subsequent
armed with organ-specific peptides, which enable them to home infection, the cranberry with oxidation resistance has long been a
in on target organs, including prostate, and assure efficient and topic of concern for the prevention of UTIs and bacterial
stable eradication of infections (Gorski et al., 2015). Phages can prostatitis (Howell et al., 1998; Habash et al., 1999). Moreover,
penetrate rat prostate tissue after their intravenous administration some authors have reported that the flavonoid, phenolics (as
(Letkiewicz et al., 2010b). Moreover, it only took a few minutes for phenolic acids, anthocyanins, and proanthocyanidins), and
phages to penetrate the circulation after rectal introduction of quercetin are the main compounds of the active components of
bacteriophages in an experiment on rabbits and mice. The blood– cranberry. The flavonoid may inhibit free radical and xanthine
phage level may be approximately two orders of magnitude higher oxidase activities; thus, it exhibits antibiotic effects and antifungal
than that with oral feeding (Letkiewicz et al., 2009). Nguyen et al. activity (Shoskes et al., 1999). The phenolics (as phenolic acids,
estimated that about 31 billion phages penetrate the intestinal anthocyanins, and proanthocyanidins) are metabolized mainly to
epithelial cell of the human body each day (Nguyen et al., 2017). hippuric acid with potent anti-adherent and anti-inflammatory
The hemorrhoidal venous plexus, extending along the whole effect (Vidlar et al., 2010). Moreover, the quercetin can reduce
rectum, connects via the hemorrhoid genital veins with the oxidative stress in prostatitis and has an anti-inflammatory effect
prostatic venous plexus, the veins of which are unidirectional (Shoskes et al., 1999). In addition, the combination of various
(Letkiewicz et al., 2010b). This feature may play a role in constituents of cranberry may improve their bioactivity due to
genitourinary pathology and may also enable drugs to reach the synergistic effects (Vidlar et al., 2010). An animal model by Kim
prostate. All previous statements provide reliable pathways for et al. indicated the preventive potential of the cranberry for CBP
phages to treat prostatitis. Moreover, rectal administration may by examining their anti-inflammatory activities (Kim et al., 2011).
also be a more efficient route for phage delivery. A randomized control trial comparing the dried powdered

cranberries (1500 mg per day for 6 months) with no cranberry inflammatory effect by an antioxidative effect and may have an
treatment in 42 participants was the first to evaluate the clinical additional (synergistic) effect with ciprofloxacin in the treatment
efficacy of cranberry in the treatment of LUTS, specifically in men of CBP (Han et al., 2008). Furthermore, the combination of S.
with BHP, elevated PSA levels, and prostatitis (Vidlar et al., 2010). repens, selenium, lycopene plus bromelain, and
Moreover, results suggested that cranberries are highly effective in methylsulfonylmethane extracts reportedly improves the success
improving prostate health by relieving PSA elevation in patients rate of levofloxacin in patients with CBP (Cai et al., 2016).
with prostatitis and by improving voiding dysfunction, Catechin, an extract of green tea, has antimicrobial effect on
independent of benign prostatic hyperplasia or C-reactive various bacteria and synergistic effect on antibiotics. In the
protein level (Vidlar et al., 2010). In addition, the diuretic treatment of CBP in an animal model, the beneficial result of
effects of the cranberry may also have contributed to the combination treatment of catechin and ciprofloxacin has shown
reduction in LUTS. Different from currently used antibiotics for that catechin may be an effective material for treating CBP, and the
prostatitis and LUTS, the main adverse effects of the cranberry are combination therapy has synergistic effect, thereby suggesting that
gastrointestinal intolerance, weight gain, and drug–cranberry it may improve clinical efficacy (Lee et al., 2005). However, given
interactions (Guay, 2009). No date can be quoted to prove that that catechin can be easily degenerated during digestion,
the cranberry can be used to treat UITs or CBP. Therefore, the nanocatechin, which is a catechin coated with hydroxypropyl
focus of the cranberry is on its application for prevention. methyl cellulose by nanotechnology, has attracted researchers’
Kim et al. reported that ginsenoid has preventive effect on attention. It reduces degeneration during digestion and enhances
patients with CBP (Kim S. H. et al., 2012). A trial comparing absorption of catechin into the body. Yoon has confirmed that
probiotics (Bifiprost(R)) + Serenoa repens 320 mg versus S. nanocatechin has better antimicrobial and anti-inflammatory
repens 320 mg alone in 120 patients with CBP (included for effects on CBP than catechin via a randomized control trial
the prevention of CBP) due to Enterobacteriaceae showed that involving a rat model (Yoon et al., 2011).
the combination of probiotics (Bifiprost(R)) and S. repens may
prevent the occurrence of episodes of CBP and ameliorate Antibiotics Combinate With Antibiotics
prostatitis-related symptoms after 6 months of therapy The improvement of eradication rates on bacterial prostatitis
(Chiancone et al., 2019). through the combination of antibiotics has also been reported
by many randomized trials. Magri et al. found that the
Combination Therapies pathogen eradication under the combination of levofloxacin
A multimodal approach to the prolonged antibiotic therapy may and azithromycin was 11% increased compared with the cases
be helpful for a higher success rate of BP. Some studies have treated with levofloxacin as a single agent (achieved in 79%)
reported various effective combination therapies for bacterial and recommended this as an interesting option in both first-
prostatitis, including plant extracts and antibiotics. referral and relapsing cases (Magri et al., 2019). Owing to a
series of distinct PK and pharmacodynamic properties
Plant Extracts Combinate With Antibiotics (including broad antibacterial spectrum, high intracellular
The properties of anti-oxidative, anti-carcinogenic, antimicrobial, accumulation in phagocytes and at sites of infected prostate,
and anti-inflammatory activities of anthocyanins have a wide biofilm-inhibiting property, immunomodulating effect, and
range of protective biological effects (Konstantin et al., 2008). inflammation-resolving activity), macrolide antibiotics are
The use of anthocyanins extracted from black soybean for CBP emerging as noteworthy options for enhancing the rates of
was evaluated by Yoon et al. by establishing a rat model in an clinical symptom improvement and pathogen eradication on
experiment involving 40 adult male Sprague–Dawley rats (Yoon the treatment of CBP (Perletti et al., 2011). A study of the
et al., 2018). Results of the trial indicated that anthocyanins with fluoroquinolone–macrolide combination therapy for CBP has
ciprofloxacin group showed a statistically significant decrease in shown that fluoroquinolones combined with macrolides can
bacterial growth and improvement in prostatic inflammation effectively eliminate pathogenic bacteria and reduce CBP
compared with the ciprofloxacin group, suggesting that symptoms, such as painful dysuria and sexual dysfunction
anthocyanins may have anti-inflammatory and antimicrobial (Magri et al., 2011b). Khryanin et al. substantiated the
effects (Yoon et al., 2018). In addition, a synergistic effect was superiority of the combination therapy of ornidazole and
observed in the anthocyanins plus ciprofloxacin group, which ofloxacin for CBP, with the background of general decline in
indicated that the combination of anthocyanins and ciprofloxacin sexually transmitted infection incidence (mostly urogenital
may obtain a higher rate of success in treating CBP (Yoon et al., trichomoniasis) (Khryanin and Reshetnikov, 2016).
2018). The report by Sohn et al. indicates that garlic may have
anti-inflammatory and antimicrobial effects. The combination of Other Combination Therapy
garlic and ciprofloxacin may be effective in treating CBP with a Administration of immunomodulators must be included in the
high success rate (Sohn et al., 2009). A prospective randomized combination treatment of CBP due to the changes in
study showed that the association of S. repens, Urtica dioica immunological parameters reflecting the depression of the
(ProstaMEV), quercetin (FlogMEV), and curcumin extracts is immune system (Kamalov et al., 2010). In a cohort of
able to improve the clinical efficacy of prulifloxacin in patients recurrent chronic prostatitis patients (RCBP) treated with
affected by bacterial prostatitis (Cai et al., 2009). Lycopene, an immunomodulator Panavir, Novikov and his coworkers
extract of tomatoes, has been reported to have an anti- reported that the addition of Panavir to standard treatment of

RCBP patients significantly improved treatment results. Panavir controlled trials are needed to provide a basis for clinical decisions
is recommended as an adjuvant in combined RCBP treatment (Schoeb et al., 2017). Transurethral using the double-balloon and
(Novikov et al., 2010). triple-channel catheter has a better clinical efficacy and has the
Androgen directly controls the growth and development of obvious advantages of being safe, effective, easy, and repeatable
the prostate gland. Thus, prostatitis may be also directly when combined with other hypurgia compared with traditional
influenced by hormone milieu, similar to the progress of BPH intravenous treatment for CBP (Huang et al., 2003). Some case
and PCA. Therefore, the effects of androgen deprivation on the reports showed that injecting antibiotics directly into the prostate
treatment of CBP were investigated in rats. Result of the trial gland was obviously effective, but further research evidences are
reported by Seo et al. showed that the finasteride and levofloxacin needed to accept this approach.
groups showed significant decreases in bacterial growth and
great improvements in prostatic inflammation compared with
the control group. This finding suggested that androgen
deprivation is an effective modality in treatment of CBP, and
CONCLUSIONS
the combination of finasteride and levofloxacin may be one of the Although global medical technology is rapidly developing in the
effective treatment modalities (Seo et al., 2003). In addition, Lee new century, there is still a long way to go in the prevention and
used an animal model and suggested that finasteride may have a treatment of bacterial prostatitis especially chronic bacterial
preventive effect on development of CBP, although there is no prostatitis. There is a relationship between ABP and CBP.
consensus yet on the mechanism of this effect (Lee et al., 2011). Approximately 10% of ABP will progress to CBP. Treatment of
Apart from the aforementioned combination therapy, Aliaev CBP is complicated due to the presence of multidrug-resistant
et al. reported the significant rising of efficacy in treating CBP bacteria, EBSL-producing E. coli, biofilms-producing bacteria, and
with the combination of antibacterial and vardenafil (Aliaev the shift in bacterial etiology. Therefore, appropriate and
et al., 2008). Moreover, the interaction between levofloxacin personalized treatment schedule after bacterial culture and drug
and diclofenac sodium has been proved by Fayyaz et al. susceptibility test is recommended instead of empirical medication.
(Fayyaz et al., 2015). Studies have shown that selenium New therapeutic strategies including fosfomycin, therapeutic
decreased bacterial infection significantly, and the therapy strategy and combination therapies have led to a dramatic
administered by both selenium and an antibiotic was more increase in bacterial-eradication rates and a qualitative
effective than the therapy that used only one of the agents to improvement in patients’ quality of life. Although the
hinder bacterial infection on prostate tissue (Kim H. W. management of bacterial prostatitis is difficult at present, this
et al., 2012). article aims to give some new treatment ideas to urologist to
replace traditional treatment. Further research into risk factors,
pathogenesis, diagnosis, prevention, and treatment should be
OTHER TREATMENT REGIMENS conducted in the future to address the current challenges.
Bacterial prostatitis will be no longer a common disease that
The confirmation that a low-intensity electromagnetic radiation confuses doctors and patients.
in the microwave range with a frequency of 1 GHz has anti-
inflammatory and trophic effects in a number of inflammatory
diseases provides a basis for resonance-microwave therapy for
CBP. Furthermore, beneficial effect of the low-intensity AUTHOR CONTRIBUTIONS
resonance-microwave therapy is seen on the levels of blood
SX searched the literature and conceived and wrote the review. LX,
proinflammatory cytokines in patients with CBP. The present
DW, ZZ, LY, TY, CL, WG and FB critically appraised the literature
study has demonstrated that resonance-microwave therapy
and made a intellectual contribution to the work. All authors
increased clinical efficacy of patients with CBP compared with
approved the final version of the manuscript for publication.
baseline drug therapy. Therefore, low-intensity electromagnetic
radiation with a frequency of 1 GHz is confirmed to be feasible
for the treatment of CBP (Kiyatkin et al., 2015).
Studies have suggested that microbubble-mediated ultrasound FUNDING
irradiation significantly increased the permeability of prostate
tissue and the effective concentrations of drugs in local tissue (Li The present study was supported by the National Natural Science
et al., 2012; Liu et al., 2013). In addition, Yi et al. have Foundation of China (grant no. 81560419 and no. 81960512)
demonstrated that the effect of inhibiting inflammation and and the Natural Science Foundation of Jiangxi (grant
reducing TNF-alpha and IL-1beta expressions on the prostate no. 20151BAB205047).
tissues can be observed by microbubble-mediated ultrasound-
induced accumulation of bone marrow mesenchymal stem cell
(BMMSCs), thereby suggesting that this method may be effective ACKNOWLEDGMENTS
for CBP (Yi et al., 2016). Schoeb et al. performed a systematic
literature search and suggested that surgical therapy of CBP might The authors thank all the people who support investigators to
be a viable option. However, further evidence and randomized complete this review.

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mediated ultrasound promotes accumulation of bone marrow mesenchymal absence of any commercial or financial relationships that could be construed as a
stem cell to the prostate for treating chronic bacterial prostatitis in rats. Sci. potential conflict of interest.
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bacterial prostatitis rat model. J. Infect. Chemother. 17, 189–194. doi: 10.1007/ License (CC BY). The use, distribution or reproduction in other forums is permitted,
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Yoon, B. I., Kim, S., Han, D. S., Ha, U. S., Lee, S. J., Kim, H. W., et al. (2012). Acute original publication in this journal is cited, in accordance with accepted academic
bacterial prostatitis: How to prevent and manage chronic infection? J. Infect. practice. No use, distribution or reproduction is permitted which does not comply with
Chemother. 18, 444–450. doi: 10.1007/s10156-011-0350-y these terms.

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published: 30 April 2020

Pharmacological Interventions for

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Pathogenesis and Pathogenic Differential Diagnosis

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FIGURE 1 | Treatment algorithm for acute bacterial prostatitis.

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