2009: Antibiotic use in prostatic disease in dogs Antibiotic use in prostatic disease in dogs 1 M. V. Root Kustritz 2 College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA 3 Abstract 4 Knowledge of pharmacokinetics of currently available antibiotics permits 5 veterinarians to choose antibiotic therapy based on microbial culture and sensitivity 6 results and ability of various classes of antibiotics to readily distribute through prostatic 7 tissue. This may replace other diagnostic tests used to support antibiotic choice, such as 8 measurement of pH of ejaculated prostatic fluid. 9 Keywords: Prostate, prostatitis, fluroquinolone 10 Introduction 11 The prostate is the only accessory sex gland of dogs. It is a retroperitoneal organ, 12 encircling the neck of the urinary bladder. It is bilobed with a palpable median raphe. In 13 smaller breed and younger dogs, it is palpable per rectum. It may be difficult to palpate 14 per rectum in large or giant breed dogs of any age, and in dogs with age-related increase 15 in prostate size and subsequent cranial positioning of the prostate and urinary bladder. 16 The prostatic capsule is thick and contains smooth muscle fibers, some as an 17 extension of muscle fibers from the wall of the urinary bladder. Some believe there is no 18 such thing as a true prostatic capsule; one study evaluating prostate histology after 19 prostatectomy in men with prostatic carcinoma instead defined a fibromuscular band of 20 varying thickness that was an inseparable continuation of the prostate stroma.1 The 21 prostatic capsule may be more of a functional than a histologic entity. 22 81 The canine prostate is made up of lobules of secretory tissue separated radially by 23 bands of connective tissue. These lobules are larger and contain more secretory tissue in 24 the dorsal and lateral areas of the prostate than in the ventral portion.2 There is little 25 smooth muscle and less stromal tissue in the canine prostate than in the human prostate. 26 The human prostate also can be separated into three distinct histologic zones (peripheral, 27 transitional, and central); these zones are not evident in dogs.3 28 The primary blood suppy arises via the internal pudental artery as the paired 29 prostatic arteries. The right and left lobes of the prostate are vascularized independently, 30 with the prostatic artery on each side separating into cranial, middle, and caudal arteries. 31 In general, vascularity is poor on the ventral prostate surface compared to the rest of the 32 gland.4 33 Clinical prostatitis 34 In men, prostate infection or inflammation is classified as acute infectious 35 prostatitis, chronic infectious prostatitis, non-infectious chronic pelvic pain syndrome, or 36 asymptomatic prostate inflammation.5,6 In dogs, acute and chronic prostatitis are 37 recognized disease entities, with prostatic abscessation generally considered a companion 38 to either. Chronic prostatitis without abscessation will be the focus of this discussion. 39 Chronic prostatis occurs in the presence of some other prostate disease. The 40 normal canine prostate is protected from ascending infection by anatomic, functional, and 41 immunologic barriers, including secretion of prostatic fluid and urine flow, urethral 42 peristalsis, formation of a urethral high pressure zone at the area of the prostate, and 43 antibacterial properties of prostatic fluid.7,8 Likelihood of infection is increased by any 44 process that increases the number of bacteria in the periprostatic urethra or urinary 45 82 bladder, or that compromises local or systemic immune response.9 Specific examples 46 include urolithiasis, urethral neoplasia, urinary tract infection, squamous metaplasia of 47 the prostate due to hyperestrogenism with subsequent decrease in prostate secretion, and 48 concurrent prostate diseases such as benign prostatic hypertrophy (BPH) or neoplasia.7 49 The class of organism most often associated with chronic prostatitis in dogs is the 50 Gram negative Enterobacteriaciae, including E. coli, Klebsiella sp., and Proteus sp. Other 51 bacterial organisms reported include Pseudomonas aeruginosa, Staphylococcus aureus, 52 and Brucella canis.10-12 Mycoplasma has been reported as a cause of chronic prostatitis,11 53 as has blastomycosis.13 Bacterial organisms implicated in human prostatitis are the same 54 as those in dogs. A complicating factor in human medicine, which may occur in 55 veterinary medicine, is formation of biofilms, a matrix of bacteria and polysaccharide that 56 permits creation of antibiotic-resistant microcolonies within tissue.14 57 Clinical signs are mild, with disease often inapparent. Reported clinical 58 presentations include infertility, poor semen quality, and signs of associated prostate 59 disease such as dripping of bloody fluid from the penis in dogs with concurrent BPH.12 60 Diagnosis is via rectal palpation, imaging, and collection of samples of prostatic 61 tissue or fluid for cytology or culture. Rectal palpation is not an accurate diagnostic test; 62 in one study of 500 dogs, rectal palpation permitted correct identification of prostate 63 disease in only 53% of cases.15 Rectal palpation can be used to judge prostate size and to 64 assess for a pain response, which usually will be absent in dogs with chronic disease. 65 There are no pathognomic changes visible by ultrasound that permit definitive diagnosis 66 by imaging alone.16 Most often the infected prostate is described as locally to diffusely 67 hyperechoic.17 Ultrasound may be best used to guide sample collection; ultrasound-68 83 guided fine-needle aspirate has been reported to be 75% accurate in identifying 69 prostatitis.18,19 70 Culture of prostatic fluid or tissue is required for definitive diagnosis of 71 prostatitis. Culture of ejaculated prostatic fluid is sensitive but not specific as it may be 72 contaminated with organisms from the urinary tract.20 Results from culture of prostatic 73 fluid correlated well with culture of prostatic tissue in only 80% of instances in one 74 study.21 Similarly, presence of inflammatory cells in ejaculated prostatic fluid is not well 75 correlated with culture results.21,22 For these reasons, cytology and culture of prostatic 76 tissue is preferred when possible. The only reported side-effect of fine-needle aspirate of 77 the prostate is transient hematuria.23 78 Treatment involves management of concurrent prostatic or urinary tract disease 79 and antibiotic therapy, as described in detail below. It has been well demonstrated that 80 castration hastens resolution of chronic prostatitis in dogs without prostatic neoplasia as 81 an underlying cause of disease.11,24 Medical treatment of underlying BPH with 82 finasteride may hasten resolution of disease; the author is unaware of studies evaluating 83 effect of finasteride therapy as a component of treatment for prostatitis in dogs. 84 Antibiotic pharmacokinetics relative to the prostate 85 Antibiotics may be characterized by their absorption, distribution, metabolism, 86 and excretion. Factors that affect these processes include lipid solubility, molecular 87 weight, and ionization of the drug molecule, and degree to which the drug is bound to 88 protein in circulation. For antibiotics to penetrate tissue, they must be able to pass 89 through the lipid-rich cell membrane, either by active transfer or diffusion. Since most 90 antibiotics move into cells passively, lipid solubility and size of the molecule are crucial 91 84 determinants of ability to penetrate tissue. Environmental pH alters ionization of the cell, 92 which also affect permeability as ionized drug cannot pass through the lipid bilayer. 93 Finally, drug that is bound to protein in serum is unavailable compared to drug that is 94 dissolved and can freely cross cell membranes.25,26 95 Ionization and trapping of drugs due to altered pH has long been upheld as a 96 component of the decision regarding which antibiotic to choose for treatment of chronic 97 prostatitis. The premise is that because charged (ionized) molecules cannot cross the cell 98 membrane and because there may be a pH gradient from serum into prostatic tissue as 99 disease develops within the prostate, uncharged molecules will equilibrate across that 100 membrane but charged molecules will get trapped on one side or the other. If you could 101 trap molecules within the tissue, you’d get a higher concentration of drug on that side 102 (uncharged plus charged portions of the total drug present).26 Knowledge of the pKa, or 103 ionization constant, would permit one to choose an appropriate antibiotic based on pH of 104 prostatic fluid. The value of this premise is decreased in small animal practice as it has 105 been demonstrated that pH of canine prostatic fluid does not significantly change in the 106 presence of prostate disease,21 and because of the availability of antibiotics that can 107 ionize at either acicid or alkaline pH. 108 Fluoroquinolones 109 Fluoroquinolones are the preferred class of antibiotics for treatment of chronic 110 infectious prostatitis in humans. The fluoroquinolones are bactericidal via inhibition of 111 DNA gyrase, which is necessary for DNA replication and repair.25 They are well 112 distributed throughout the body because they are lipid soluble and are amphoteric, with 113 both acidic and alkaline ionization constants.27-29 Fluoroquinolones also move well into 114 85 biofilms, lessening chance of persistent or recurrent infection.27 Products available for 115 oral use in dogs include enrofloxacin (Baytril®; Bayer Animal Health, Shawnee Mission, 116 KS, USA), ciprofloxacin (Cipro®; Schering-Plough, Kenilworth, NJ, USA), 117 marbofloxacin (Zeniquin®; Pfizer Animal Health, New York, NY, USA), orbifloxacin 118 (Orbax®; Intervet/Schering-Plough Animal Health; Summit, NJ, USA), and difloxacin 119 (Dicural®; Fort Dodge Animal Health, Ft. Dodge, IA, USA). Of these compounds, 120 enrofloxacin shows superior movement into canine prostatic tissue, followed by 121 ciprofloxacin and marbofloxacin.28,30-32 122 Macrolides 123 The macrolide antibiotics are bactericidal or bacteriostatic, depending on bacterial 124 species.25 Erythromycin is lipid-soluble but is quickly broken down after oral 125 administration and is highly protein bound.27 Azithromycin concentrates in phagocytes 126 and so is carried into tissue, from which it is slowly released, permitting less frequent 127 dosing.27,33-35 It has been demonstrated to penetrate the prostate well in humans.27 There 128 are no veterinary formulations of azithromycin available as of this writing. 129 Chloramphenicol 130 Chloramphenicol is bactericidal or bacteriostatic, depending on bacterial 131 species.25 It is very lipid-soluble and not highly protein bound.27 Because tissue 132 concentrations generally are well below those in serum, high doses must be used, raising 133 concerns about toxic effects, including myelosuppression, with long-term use.7 134 Trimethoprim-Sulfas 135 Trimethoprim-sulfa combinations are bacteriostatic as they inhibit DNA 136 replication.25 These drugs are well absorbed orally and penetrate prostate tissue well.27 137 86 Concerns of long-term use include keratoconjunctivitis sicca, anemia, and acute 138 neutrophilic hepatitis.27 The approved veterinary product for dogs is trimethoprim-139 sulfadiazine (Tribrissen®; Intervet/Schering-Plough). 140 Other antibiotics 141 Penicillins and cephalosporins are poorly lipid-soluble and do not penetrate the 142 chronically infected prostate.27 Aminoglycosides (amikacin, gentamycin) show 143 variability tissue penetration and potential toxicity with long-term use.27,36 Doxycycline 144 penetrates prostate tissue better than tetracycline but is not commonly used.27 145 Metronidazole (Flagyl®; Pfizer, Inc, New York, NY, USA) may be useful if anaerobic 146 infection is a component of disease; it is a lipid-soluble antibiotics that is well absorbed 147 orally and is not highly protein bound.27 Neurologic signs and gastrointestinal signs may 148 be seen as side-effects.27 149 Conclusion 150 The primary factor governing antibiotic choice must be the result of culture and 151 sensititivity testing, preferably of prostatic tissue. The chosen antibiotic should be 152 administered for 4 to 6 weeks, with rechecks of prostatic fluid or tissue culture at 7 days, 153 one month and 6 months after completion of therapy.29,37 Antibiotic resistance may be a 154 growing concern with wide use of fluoroquinolone antibiotics;38 for this reason an effort 155 should be made to decrease risk of recurrence. Concurrent disease of the urinary tract or 156 prostate must be addressed, including a recommendation for castration in dogs with BPH 157 and recurrent or persistent prostatitis. 158 References 159 87 1. Ayala AG, Ro JY, Babaian R, et al: The prostatic capsule: does it exist? Its 160 importance in the staging and treatment of prostatic carcinoma. Am J Surg Path 161 1989;13:21-27. 162 2. Stefanov M, Martin-Alguacil N, Martin-Orti R: Distinct vascular zones in the 163 canine prostate. Micro Res Tech 2000;50:169-175. 164 3. 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