primary complaints of straining to urinate, bloody urine, and decreased appetite. The owner said she

Transcription

1 Hillary Chase ID# Clinical pharmacology It s so nice to read an excellent paper. A Prostatitis Champ a 4 year old, male intact, 60 pound, golden retriever, presented to the clinic with the primary complaints of straining to urinate, bloody urine, and decreased appetite. The owner said she first noticed a red tinged color to Champ's urine about one week ago, and that he started straining during urination within the last few days. Champ is currently up to date on vaccinations and receives monthly interceptor. About one year ago, Champ had been diagnosed with benign prostatic hyperplasia and was successfully treated with megestrol acetate for an 8 week duration. At that time, Comment [jrw1]: A little hard to reconcile with your title (suppose that depends on what success means eh?) the owner chose not to castrate Champ in hopes to use him for breeding. On physical exam, Champ was found to have a mild fever of 103 F. Rectal examination revealed a moderately enlarged prostate that seemed painful on palpation. A hemorrhagic discharge was noted coming from the prepuce. Overall, Champ appeared bright and alert, with no other abnormalities noted on physical exam. Urine collected by cystocentesis, prostatic fluid obtained by prostatic wash, and a sample of blood were submitted for laboratory analysis. The following abnormalities were noted: 1. Hypokalemia, potassium=3.2 meq/l 2. Leukocytosis characterized by a neutrophilia and a left shift, WBC=18,000 Segs=13,000 Bands= Pyuria WBC= 6/HPF 4. Hematuria RBC= 70/HPF 5. Bacteriuria 6. Proteinuria 2+ On ultrasound, the prostate appeared symmetrically enlarged with a uniform increase in echogenicity. No cystic lesions were seen. Cytology from the prostatic wash revealed an excess of inflammatory cells and numerous bacteria. Samples of the urine and post-massage prostatic wash were

2 sent off to a diagnostic laboratory for culture and sensitivity using soft tissue interpretation. Pending culture results, Champ was diagnosed with bacterial prostatitis. The total cost for exam, diagnostic work up, and pending cultures was $265. The goals for Champ's therapy included the following: 1. To start initial medical therapy with a broad spectrum antimicrobial. 2. To base therapy on culture and sensitivity once results have returned. 3. To castrate Champ in order to increase the chance of a cure and to help prevent relapse. 4. To evaluate success of therapy by culture after antimicrobial treatment is completed. Pending culture and sensitivity, Champ was started on trimethoprim sulfamethoxazole at a dose rate of 30 mg/kg/day (two 480 mg tablets.) Trimethoprim sulfamethoxazole was empirically chosen because studies have shown that the drug is capable of diffusing into the prostate and is capable of producing prostatic concentrations effective against most of the common isolates in prostatitis, including E. coli (6). The cost for dispensing and the initial three days of therapy was $5.50. The Comment [jrw2]: This is two drugs. My understanding of the literature is that trimethoprim penetrates the normal prostate, sulfamethoxazole does not. I would argue, therefore, that the drug TMP/SMX does NOT cross the barrier. owners agreed to castration and surgery was scheduled. The decision was made to delay castration for 2 weeks, since castration may decrease antimicrobial delivery to the prostate by decreasing local blood supply and may alter local defense mechanisms (3). Castration plays an important part of therapy for prostatitis by decreasing the amount of functional prostatic tissue, helping to decrease the incidence of Comment [jrw3]: This makes sense but, you should be aware that lots of things in the Bristol Handbook are pretty goofy (never been one of my favorite references). recurrent infections. The objective of antimicrobial therapy in this case was to deliver effective concentrations of antimicrobials to the interstitial tissues of the prostate gland. Delivery of antimicrobials to the prostate Comment [jrw4]: Nicely stated. can pose a challenge due to the blood-prostate barrier. This barrier is made up plasma membranes with a hydrophobic core and small lipoprotein aqueous channels embedded within the membrane (1). There is no mechanism for active transport of antimicrobials across this membrane, so delivery of drugs to the site of infection relies on passive diffusion. Ideally, antimicrobials should possess the following characteristics to allow passive diffusion into the prostate: high lipid solubility, non-ionized, small, and

3 limited protein binding (4). Since the normal canine blood ph is 7.2, basic drugs are more ideal since Deleted: Ph they will be less ionized in circulation. Limited protein binding is desirable, since it will increase the amount of free drug available for simple diffusion into the prostate. In acute prostatitis, the blood prostatic barrier may be disrupted which permits most antimicrobials to penetrate the inflamed prostatic tissue. However, with treatment the prostatic barrier is reestablished, making the previously mentioned characteristics essential in order to prevent relapse of infection. In chronic prostatitis, the barrier may be functionally intact before any treatment is given (3). The pka of the antimicrobial is an important feature that can be taken advantage of through the concept of ion trapping. The normal canine blood Ph is 7.4, where as the normal prostatic fluid Ph is 6.2. Depending on the pka, basic drugs can be used that will be non-ionized in the blood, allowing them to passively diffuse into the prostate (6). Once they enter the prostate, the drug becomes ionized and is trapped on the prostatic side of the blood prostatic barrier, effectively increasing the prostatic concentration of the drug compared to the serum concentration. With the treatment of prostatitis, the capability for the antimicrobial to be bactericidal is considered important, to improve the likelihood of eliminating the infection from the prostate and to prevent relapse. The site of the infection makes it unlikely for the bacteria to be eradicated by host Comment [jrw5]: This is all true and worth considering. You should be aware that there is another side to the debate, specifically that ionized drug may not be active (only unionized drug can diffuse into bacteria). This is also part of my argument about Tribrissen. Trimethoprim qualifies for this ionization, sulfamethoxazole (far as I know) does not. mechanisms alone. Although prostatitis itself is not life threatening, if not treated effectively prostatitis may lead to the formation of a life threatening prostatic abscess, further warranting the need for bactericidal activity (9). Culture and sensitivity was considered essential in this case, due to the fact that prostatitis is a UTI complicated by deep infection, in which efficacy of treatment is more dependent on the antimicrobial compound chosen. A greater urgency for a cure also exists than for a simple noncomplicated UTI. The susceptibility test chosen was tube dilution mic, based on a soft tissue interpretation. Although prostatitis is considered a UTI, the infection is located within the prostatic parenchyma, making serum concentrations a better indicator of susceptibility than urine concentrations.

4 Tube dilution was chosen over agar disk diffusion in order to receive information on relative susceptibility that could be used to help guide therapy. Three days after the prostatic fluid sample and urine were submitted, results of the culture and sensitivity came back with E. coli as the only isolate. The following results were found on the antimicrobial susceptibility report: Drug Susceptibility Range Break Point Amikacin 8 S :32 Amoxicillin/Clavulonic acid >16 R 0.5/0.25:16/8 8/4:16/8 Ampicillin/sublactam ---R 8/4-16/8 8/4:16/8 Ampicillin >16 R :16 Cefazolin 8 S :16 Cefoxitin 16 I :16 Ceftazidime 1 S :16 Ceftriaxone <4 S :16,32 Cefuroxime >16 R :16 Cephalothin ---R :16 Ciprofloxacin <0.6 S :2 Gentamicin 1 S :8 Lomefloxacin <0.5 S :4 Mezlocillin >64 R :32,64 Nitrofurantoin ---S :64 Norfloxacin ---S 4-8 4:8 Ofloxacin <0.25 S :4 Piperacillin >64 R :32,64 Sulfasoxazole ---S :>256 no I Tetracycline 0.5 S :8 Ticarcillin/ Clavulanic acid >64 R 4/2-64/2 16/2:32/2,64/2 Trimethoprim/ Sulfamethoxazole ---S 0.5/9.5 2/38:>2:38 no I Deleted: Ceftriazone Deleted: l Deleted: Oxfloxacin Deleted: Sulfasoxizole Deleted: Clavulonic Deleted: Sulfamethoxizole Based on resistance found on sensitivity results, the following antimicrobials were eliminated as therapeutic choices: Amoxicillin/Clavulonic, Ampicillin/sublactam, Ampicillin, Cefuroxime, Cephalothin, Mezlocilllin, Piperacillin, and Ticarcillin/ Clavulonic acid. Many of the remaining susceptible antimicrobials could be eliminated as therapeutic options, based on chemical properties that would be associated with poor diffusion into the prostate. As a group the cephalosporins are weak acids with a low pka, poor lipid solubility, and variable protein binding (1). All of these characteristics prevent cephalosporins from reaching minimal inhibitory concentrations within the prostate.

5 Nitrofurantoin, although lipid soluble, is a weak acid that does not readily diffuse into the prostate. The aminoglycosides, including amikacin and gentamicin, do not penetrate prostatic tissue well and can't be used orally for systemic effects (1). Oral antimicrobials were preferred in Champ's case since his infection is not currently life-threatening and he was bright and alert on physical exam. Oral antimicrobials would also allow easy at home administration. Although tetracycline seemed to show good susceptibility in this case and is lipophilic, studies have shown that the drug concentration of tetracyclines in the prostate fails to reach more than 20 percent of the plasma concentration (6). This is Comment [jrw6]: Even minocycline (one I ve always kept in the back of mymind for these)? most likely due to their amphoteric nature that causes them to dissociate primarily as acids. After consideration of the susceptibility and the ability to reach the site of infection, the two main antimicrobial groups left as possible therapeutic choices were the quinolones and trimethoprim sulfas. Both the quinolones and trimethoprim sulfas have the potential to be bactericidal and exhibit many of Deleted: h the ideal characteristics required for passive diffusion into the prostate. Trimethoprim by itself exhibits all of the ideal characteristics required for passive diffusion into the prostate: lipid solubility, dissociates as a base with a pka of 7.3, and exhibits moderate protein binding (~45%.) Studies have shown that prostatic levels of trimethoprim reach 3-11 fold higher levels than those found in plasma(6). Although the sulfa drugs have been shown to only reach low levels within the prostate, it is thought that the sulfas reach high enough levels in the prostate to still be synergistic when given with trimethoprim. Their biochemical properties and relative inexpensiveness Comment [jrw7]: Thought by some perhaps, not by me necessarily were why a trimethoprim sulfa was initially chosen for Champ's therapy. However, a trimethoprim sulfa was not chosen for continued therapy in this case due to their potential side effects and the presence of other options based on C/S. (In fact, the client had done her own research online while awaiting the C/S and was extremely concerned over the possible side effects seen with trimethoprim sulfamethoxazole). Possible adverse reactions include kerato-conjunctivitis sicca, folate deficiencies, Comment [jrw8]: With incredibly high dosage and duration. and polyarthropathies (2). Although these adverse reactions can be seen with only one dose, they are more commonly seen with prolonged administration (8). Since Champ required long term

6 antimicrobial therapy, the prolonged use of a trimethoprim sulfa was not considered ideal. The quinolones as a group are lipophilic with an amphoteric nature. Lomefloxacin, norfloxacin, ofloxacin, and ciprofloxacin represented the quinolones on the susceptibility profile in this case. Each Comment [jrw9]: Stand-in for enrofloxacin because we use human susceptibility plates. exhibited excellent susceptibility against the E. coli isolate. Although they don't satisfy all of the ideal characteristics for diffusion into the prostate, studies have shown that many of the antimicrobials in the quinolone group are capable of reaching prostatic fluid and tissue concentrations that exceed the plasma concentrations by a factor greater than one (2). With the exception of possible cartilage damage in juveniles, the quinolones are a relative safe class of drugs that were considered ideal for the prolonged administration required to treat Champ (5) Given that the client was not concerned with cost, a quinolone was chosen over trimethoprim sulfa in order to help decrease the possible adverse reactions from prolonged antimicrobial therapy. Enrofloxacin was chosen as the quinolone of choice in this case since it is a readily available veterinarian approved quinolone that is available in a tablet form. Champ was started on enrofloxacin (Baytril) at a dose rate of 5 mg/kg/day to be divided into two equal doses a day for a duration of 5 weeks. At a weight of 60 pounds, the dose required for Champ was 136 mg per day. Enrofloxacin tablets are available in 22.7, 68, and 136 mg tablets. A total of 70, 68 mg tablets were dispensed with directions to give one tablet by mouth, twice a day. Enrofloxacin naturally has a bitter taste, so the flavor tab version was chosen to increase palatability in case the owner would require breaking the tablet into food for administration. An enteric coated form exists that hides the bitter flavor; however, this form should not be broken up into food since this will increase the bitterness and the animal will most likely not eat the medication. The owner was advised not to administer vitamin supplements to Champ within 2 hours of giving the enrofloxacin, since iron, zinc, magnesium or aluminum may bind enrofloxacin and prevent GI absorption (5). The cost of each 68 mg tablet was about $1.69, so the total cost of treatment (70 tablets) and dispensing was $ The owner was advised that even though signs may appear to clinically resolve during treatment, that it was important to give the whole regiment of antibiotics to Champ to prevent relapse

7 of the infection. Champ was expected to start showing improvement within the first week of antimicrobial therapy. Castration was performed two weeks after the start of the antimicrobial treatment without complications. The mechanism of action of enrofloxacin is deactivation of the bacterial DNA gyrase, which is required for bacterial DNA transcription. This antimicrobial seems relatively safe in animals, since the mammalian DNA gyrase enzyme is shaped differently. With doses ten times the recommended dose, vomiting and diarrhea may be seen, but are typically not seen with normal doses (5-20mg/kg.) In immature animals, flouroquinolones are associated with joint cartilage damage, but is only seen in growing dogs. Enrofloxacin may lower the seizure threshold in dogs and should be avoided in dogs with known seizure disorders. As an adult with no history of seizures, the side effects expected in Comment [jrw10]: This an if possible contraindication. (I d risk it to save a dog from a life-threatening infection). Champ were predicted to be minimal as long as the owner administered the medication as directed. In order to monitor the success of treatment, Champ returned to the clinic one week after he completed his antimicrobial therapy. The owner reported complete resolution of clinical signs. A post massage prostatic fluid sample was obtained and sent off for culture. Results of the culture were negative for any bacteria, documenting success of the antimicrobial treatment. References 1. Charalabopoulos, Konstantin, et al. Penetration of Antimicrobial Agents into the Prostate Chemotherapy 49 (2003) Dorfman, Mark, Barsanti, Jeanne, and Steven Budsberg. Enrofloxacin concentrations in dogs with normal prostate and dogs with chronic bacterial prostatitis American Journal of Veterinary Research 56 (1995): Johnston, Dudley, ed. The Bristol Veterinary Handbook of Antimicrobial Therapy. 2 nd ed. Philadelphia: University of Pennsylvania, Kutzler, Michelle, and Amy Yeager. Prostatic Diseases. In Ettinger, SJ, Feldman, EC, eds. Textbook of Veterinary Internal Medicine. 6 th edition, Elsevier Saunders, St. Lois, 2005; pp

8 5. Mar Vista Animal Medical Center. Enrofloxacin Online 30, Mar Meares, Edwin. Prostatitis: Review of Pharmacokinetics and Therapy Reviews of Infectious Diseases 4 (1982): Struthers, Keith, and Roger Westran. Clinical Bacteriology. London: Manson Publishing Ltd Veterinary Information Network, Inc. Trimethoprin Sulfa Pet Pharmacy. Online. 30, Mar Wallace, Melissa. Diagnosis and Medical Management of Canine Prostatic Disease Atlantic Coast Veterinary Conference