J Vet Intern Med 2007;21:990–995

Clinical Efficacy and Palatability of Pradofloxacin 2.5% Oral Suspension for the Treatment of Bacterial Lower Urinary Tract Infections in Cats

Annette Litster, Susan Moss, Mary Honnery, Bob Rees, Markus Edingloh, and Darren Trott

Background: Pradofloxacin is a 3rd generation veterinary fluoroquinolone designed to restrict the emergence of antimicrobial resistance during therapy. Hypothesis: Pradofloxacin 2.5% oral suspension is a safe, efficacious, and palatable treatment for bacterial urinary tract infections (UTI) in cats. Animals: Seventy-eight cats presented with lower urinary tract signs and were positive on bacterial culture of urine. Methods: Cats were allocated into 3 treatment groups depending on bacterial susceptibility results: pradofloxacin (n 5 27), doxycycline (n 5 23), or amoxicillin-clavulanic acid (n 5 28). All antimicrobials were presented in palatable liquid form. Posttreatment urine specimens were collected after completion of the course of treatment and submitted for bacterial culture and sensitivity. Owners were questioned before and after treatment about their experiences with administering oral medication to their cats. Results: Posttreatment urine culture was negative in all cats in the pradofloxacin group, but there were 3 treatment failures in each of the other groups. Owners’ perceptions of the difficulty of administering oral medication to their cats was more positive posttreatment than pretreatment (P 5 .001; P , .001). There was no difference in palatability among the treatment groups (P . .05). Conclusions and clinical importance: We conclude that pradofloxacin 2.5% oral suspension is a highly effective and safe antimicrobial treatment for bacterial lower urinary tract infection in cats, and that the palatable formulation optimizes owner compliance. These findings make pradofloxacin a useful addition to the veterinary formulary. Key words: Bacterial cystitis; Cats; Fluoroquinolone.

lthough clinical signs of lower urinary tract disease a range of canine and feline urinary tract pathogens, A (eg, dysuria, stranguria, pollakiuria, and hematu- including Escherichia coli and Staphylococcus spp.9 ria) are common in feline practice,1 bacterial urinary The aim of this controlled clinical trial was to assess tract infections (UTI) in cats are relatively rare.2 A the clinical efficacy and palatability of pradofloxacin variety of physical and mucosal defence mechanisms in 2.5% oral suspension compared to 2 other commonly the feline urinary tract, including highly concentrated prescribed antimicrobials (doxycycline and amoxicillin- urine, present a relatively hostile environment for clavulanic acid) for the treatment of feline bacterial bacterial growth.3,4 Studies consistently have shown that lower UTI. bacterial cystitis affects less than 3% of cats presenting with lower urinary signs.5–7 However, bacterial UTI are Materials and Methods important to recognize in feline practice because they can be cured with appropriate antimicrobial therapy. By Animals contrast, current treatments for idiopathic feline in- Approval for this study was granted by The University of terstitial cystitis, which has the same presenting signs as Queensland Animal Ethics Committee (Approval Number: SVS/ bacterial cystitis and is commonly diagnosed in practice, 131/05/BAYER). Urine specimens collected by cystocentesis were are only palliative.8 submitted from cats presenting at a number of participating Pradofloxacin is an 8-cyano-fluoroquinolone devel- veterinary clinics in the Brisbane, Queensland area. Only cats that oped to treat bacterial infections in dogs and cats.9 presented with clinical signs of urinary tract disease (eg, dysuria, stranguria, pollakiuria, and hematuria) and determined to have Molecular substitutions at positions C-7 and C-8 have positive bacterial urine cultures were included in the study. greatly enhanced the bactericidal activity of pradoflox- Signalment and clinical history were obtained for each cat, and acin compared to earlier fluoroquinolones, especially for a full urinalysis and bacterial culture were performed on all urine 9 pathogens with reduced fluoroquinolone susceptibility. specimens. After bacterial culture-positive status was confirmed, It has been shown in vitro to be highly active against cats were allocated into 1 of 3 antimicrobial treatment groups: pradofloxacin 2.5% oral suspension (recommended dosage 0.2 mL/ From the School of Veterinary Science, The University of kg q24h for a minimum course of 10 days); 100 mg/g doxycycline Queensland, Brisbane, Australia (Litster, Moss, Honnery, Trott); monohydrate paste (recommended dosage 5 mg/kg as a loading and the Bayer Health Care, Animal Health Division, Australia Ltd, dose, followed by 2.5 mg/kg q12h for 2 doses, and then a mainte- Brisbane, Australia (Rees); and the Bayer Animal Health, nance dosage of 2.5 mg/kg q24h for a minimum of 10 days); or Leverkusen, Germany (Edingloh). 62.5 mg/mL amoxicillin-clavulanic acid oral suspension (recom- Reprint requests: Annette Litster, School of Veterinary Science, mended dosage 62.5 mg/cat q12h for a minimum of 10 days), The University of Queensland, St. Lucia, Queensland, 4072 depending on results of antimicrobial susceptibility testing. If the Australia; e-mail: [email protected]. bacterial isolate was susceptible to more than 1 of the 3 Submitted February 12, 2007; Revised April 4, 2007; Accepted antimicrobials, the cat was allocated to the group with the fewest May 3, 2007. enrolees. Urine culture and urinalysis were repeated posttreatment, Copyright E 2007 by the American College of Veterinary Internal a minimum of 2 days after the antimicrobial course was completed. Medicine Urine was collected by cystocentesis if possible, otherwise a sterile 0891-6640/07/2105-0015/$3.00/0 urinary catheter was inserted after surgical preparation of the Pradofloxacin for Urinary Tract Infection in Cats 991 perineum. The pupillary-light-response reflex of all cats assigned to Comparisons between scored data were made by means of the pradofloxacin treatment group was examined twice during the the Kruskal-Wallis test for multiple independent groups. Compar- course of antimicrobial therapy. isons of multiple groups of independent data that fulfilled parametric assumptions were compared by means of ANOVA. Urine Culture and Urinalysis Chi-squared tests were used to compare binary data in contingency tables. On receipt, all urine specimens were cultured as described previously.10 Antimicrobial susceptibility patterns for all isolates were determined by the Kirby-Bauer disk diffusion method for Results a range of antimicrobials according to the guidelines of the Clinical Animals Laboratory Standards Institute.11,12 A minimum of 2 mL of urine was centrifuged at 3,000 3 g for Eighty-seven cats met the eligibility criteria (clinical 10 minutes and urinalysis was performed on the supernatant as signs of urinary tract disease and positive bacterial urine previously described.10 culture) and were allocated into a clinical trial antimi- crobial group. Seventy-eight of the 87 cats (pradoflox- Palatability Testing acin, n 5 27; doxycycline, n 5 23; amoxicillin-clavulanic Each owner was asked to complete a questionnaire (see below) acid, n 5 28) completed the entire trial procedure, concerning their previous experiences when medicating their cat, including provision of a posttreatment urinary tract before the cat commenced the clinical trial. This questionnaire was specimen. Course-length statistics for each of the administered by veterinarians or veterinary technicians at partici- antimicrobials were as follows: pradofloxacin, range pating veterinary clinics, who recorded responses on a scoresheet. 11–30 days (median, 18 days); doxycycline, range 14– Numerical scores were allocated to responses, as shown below. The 39 days (median, 28 days); amoxicillin-clavulanic acid, same questionnaire was completed by cat owners after the clinical range 11–46 days (median, 21 days). Course length for trial, concerning their experiences when administering the clinical- the pradofloxacin group was statistically shorter than trial medication to their cats. The questionnaire used after completion of the clinical trial was administered by staff from the for each of the other 2 groups (P , .05). Table 1 reports School of Veterinary Science, The University of Queensland, and the age, sex, and breed characteristics of all cats included responses were recorded on a scoresheet. in the clinical trial at the time the pretreatment urine specimen was obtained. There was not a statistically Questionnaire significant difference among treatment groups for any of Question 1 (before the clinical trial). When giving your cat these parameters. Urine was collected by cystocentesis medication that must be swallowed, which of the following best describes your previous experience: for 75 pretreatment urine specimens (pradofloxacin, n 5 Question 1 (after the clinical trial). When giving your cat the 25; doxycycline, n 5 22; amoxicillin-clavulanic acid, n 5 clinical-trial medication that must be swallowed, which of the 28), whereas urinary catheterization was used to obtain following best describes your experience: the remaining 3 specimens (pradofloxacin n 5 2 and doxycycline n 5 1). One of the 2 specimens obtained in a. Impossible: 22 the pradofloxacin group by catheterization produced b. Have difficulty but succeed: 21 a heavy ($100,000 colony forming units/mL) pure c. Use avoidance tactics (eg, hide in food): 0 growth of E. coli, whereas the other specimen produced d. Have the occasional problem but always succeed: +1 a very light (100–1,000 colony forming units/mL) e. Never have a problem: +2 pure growth of Proteus mirabilis. The specimen ob- f. Other (please specify): Unscored tained by catheterization in the doxycycline group produced a heavy ($100,000 colony forming units/ Question 2 (before the clinical trial). When giving your cat mL) pure growth of Staphylococcus felis. Urine was medication that must be swallowed, which of the following best describes the response your cat most often displays: collected by cystocentesis for all posttreatment urine Question 2 (after the clinical trial). When giving your cat the specimens. clinical-trial medication that must be swallowed, which of the The posttreatment urine specimen in all cats in the following best describes the response your cat most often pradofloxacin group was negative for bacteria on urine displays: culture. In each of the other 2 treatment groups, there were 3 cats (doxycycline, 13.0%; amoxicillin-clavulanic a. Shows aggressive behavior (eg, growls, hisses, scratches, or acid, 10.7%) in which the posttreatment urine specimen bites): 22 was positive for bacteria on urine culture (Table 2). The b. Shows one or more of the following behaviors: gags, coughs, difference in proportions of treatment failure among will not swallow, salivates, shakes head, or spits out groups was not statistically significant (P . .05) medication: 21 Adverse events that were attributed to drug exposure c. Both (a) and (b): 23 d. Shows indifference: 0 by the attending veterinarian were not reported in the e. Shows positive behavior (purrs, rubs, or licks): +2 pradofloxacin or doxycycline groups. Three cats initially f. Other (please specify): unscored allocated to the amoxicillin-clavulanic acid treatment group developed gastrointestinal signs that were attrib- uted by the attending veterinarian to drug exposure, Statistical Analysis resulting in their exclusion from the trial. None of the StatsDirect software was used for all statistical calcula- cats in the pradofloxacin group had pupillary-light- tions. GraphPad Prism 4 software was used to draw graphs. response test abnormalities during therapy. 992 Lister et al

Table 1. Signalment and urinalysis characteristics for each treatment group at the time the pretreatment urine specimen was obtained, and the P-value for the comparison between groups.

Pradofloxacin Doxycycline Amoxicillin- Clavulanic Variable (n 5 27) (n 5 23) Acid (n 5 28) P-Value Age (median, range) 13.8, 2.0–20 11.0, 0.9–21.0 11.8, 1.0–18.8 0.94 Sex (% male) 29.6 17.4 25.0 0.60 Purebred (%) 40.7 43.5 46.4 0.91 Specific gravitya (median, range) 1.027, 1.011–1.047 1.032, 1.009–1.059 1.035, 1.010–1.060 0.19 Urine glucose (Trace, + to 4+; median, range) 0, 0–1 0, 0–1 0, 0–3 0.88 pH (median, range) 6.5, 5.0–8.5 6.5, 5.0–7.5 7, 6.0–8.5 0.08 Protein (g/L; median, range) 0.31, 0.04–5.17 0.25, 0.01–24.4 0.38, 0.10–4.29 0.45 Protein : creatinine ratio (median, range) 0.33, 0.05–17.38 0.25, 0.04–11.14 0.21, 0.04–2.19 0.42 Erythrocyte countb (/mL; median, range) 90, 10–1000 30, 10–1000 500, 10–1000 0.29 Leucocyte countb (/mL; median, range) 380, 10–1000 50, 10–1000 110, 10–1000 0.25 Casts (%) 0 4.5 0 0.29 Crystals (%) 18.5 13.6 18.6 0.88

a Only cats not receiving fluid therapy at the time of urine collection were included in specific gravity results (pradofloxacin n 5 23; doxycycline n 5 22; amoxicillin-clavulanic acid n 5 23). b Erythrocyte and leucocyte counts .1,000 cells/ mL were counted as 1,000 cell/ mL, and ,10 cells/ mL were counted as 10 cells/ mL.

Urine Culture antimicrobials including amoxicillin-clavulanic acid, clinical experience by this group has shown that, because Table 3 summarizes bacterial isolate identification of the low uropathogenicity of this strain, bacterial information in each treatment group for the pretreat- cystitis caused by MDREC is successfully treated with ment urine specimen. In the pradofloxacin group, a normal course of amoxicillin-clavulanic acid (D. Trott, a single isolate was cultured in 23 of 27 urine specimens 2007; unpublished data). The other 3 urine isolates from (85.2%) and 2 isolates were cultured from 4 specimens the cat concerned were sensitive to amoxicillin-clavu- (14.8%). In the doxycycline group, a single isolate was lanic acid. For these reasons, the cat that provided the cultured in 22 of 23 urine specimens (95.7%) and pretreatment urine specimen containing the MDREC 2 isolates were cultured from 1 specimen (4.3%). In the isolate was allocated to the amoxicillin-clavulanic acid amoxicillin-clavulanic acid group, a single isolate was group. The posttreatment urine specimen from this cat cultured in 21 of 28 urine specimens (75.0%); 2 isolates was negative on bacterial culture. were cultured from 6 specimens (21.4%); and 4 isolates were cultured from the remaining specimen (3.6%). These 4 isolates included a multidrug-resistant E. coli Urinalysis (MDREC) isolate. Even though initial susceptibility Table 1 shows urinalysis results for all cats at the time testing for the MDREC isolate showed resistance to all pretreatment urine specimens were obtained. There was

Table 2. Treatment failure information.

Bacterial isolate cultured from:

Initial Urine In-Vitro Susceptibility Posttreatment Urine In-Vitro Susceptibility Treatment Group Specimen to Trial Antimicrobial Specimena to Trial Antimicrobial Doxycycline Enterococcus faecalis Sensitive to Enterococcus faecalis Sensitive to tetracycline tetracycline Doxycycline Staphylococcus felis Sensitive to Enterococcus faecium Resistant to tetracycline tetracycline Doxycycline E. coli (haemolytic Both sensitive to E. coli (haemolytic E. coli (hemolytic strain)— strain), tetracycline strain), E. coli Intermediate susceptibility to Enterococcus faecalis (nonhaemolytic tetracycline strain) E. coli (nonhemolytic strain)— Sensitive to tetracycline Amoxicillin- E. coli Sensitive E. coli Sensitive clavulanic acid Amoxicillin- E. coli Sensitive E. coli Sensitive clavulanic acid Amoxicillin- Proteus mirabilis Sensitive Proteus mirabilis Sensitive clavulanic acid

a All posttreatment urine specimens were submitted for bacterial culture 3–8 days after completion of the course of antimicrobial treatment. Pradofloxacin for Urinary Tract Infection in Cats 993

Table 3. Bacterial isolate information for each treatment group for the pretreatment urine specimen.

Pradofloxacin Doxycycline Amoxicillin- Clavulanic Acid Bacterial Species (n, % isolatesa) (n, % isolatesa) (n, % isolatesa) Gram-negative bacilli 19, 61.3 12, 50 15, 40.5 E. coli 15, 48.4 12, 50 11, 29.7 Proteus mirabilis 2, 6.5 0, 0 2, 5.4 Proteus vulgaris 1, 3.2 0, 0 0, 0 Enterobacter aerogenes 0, 0 0, 0 1, 2.7 Pseudomonas aeruginosa 1, 3.2 0, 0 0, 0 Klebsiella pneumoniae 0, 0 0, 0 1, 2.7 Gram-positive cocci 12, 38.7 12, 50 22, 59.5 Enterococcus faecalis 3, 9.7 4, 16.7 14, 37.8 Enterococcus faecium 0, 0 1, 4.2 0, 0 Staphylococcus felis 5, 16.1 6, 25.0 7, 19.0 Staphylococcus aureus 2, 6.5 0, 0 0, 0 Staphylococcus intermedius 1, 3.2 1, 4.2 0, 0 Streptococcus bovis 1, 3.2 0, 0 1, 2.7

a Percentage of all isolates (Gram-negative and Gram-positive) for each of the treatment groups. no statistically significant difference among treatment In this study, treatment failures were reported in both groups for any urinalysis parameters. the doxycycline group and the amoxicillin-clavulanic acid group, despite the fact that cats were allocated to Palatability Testing each group on the basis of initial susceptibility of the bacterial pathogen to these agents and that course length Figure 1 shows box and whisker plots of posttrial for each of these 2 groups was longer than that of the palatability scores for each of the antimicrobial agents. pradofloxacin group. The difference in proportions of There was no statistically significant difference in treatment failure among groups was not statistically posttrial palatability scores among antimicrobial agents significant, but this result may be a consequence of (Q1, P 5 .571; Q2, P 5 .164; Kruskal-Wallis test). decreased statistical power because of small sample size. Some of the treatment failures may have been owing to Discussion poor owner compliance, because isolates in 4 of the 6 This study reports the use of a new 3rd generation posttreatment urine specimens showed in vitro suscep- fluoroquinolone (pradofloxacin) in the treatment of tibility to the original trial antimicrobial. Superinfection bacterial UTI in cats. As expected from previous studies, with a more resistant clone, either during therapy or cats with bacterial UTI were older (median, 11– shortly thereafter, may have been responsible for the 14 years), had relatively low urine specific gravity remaining 2 treatment failures, in which isolates (USG),7,13–15 and were female.7 Older cats are more demonstrated in vitro resistance or intermediate suscep- likely to have diminished defences against infection, tibility to the trial antimicrobial (Table 2). making them more susceptible to UTI,16 and the The current therapeutic standard for the empirical relatively high USG of normal cat urine acts as a natural treatment of acute uncomplicated cystitis in humans is host defence mechanism preventing bacterial UTI.16,17 trimethoprim-sulfamethoxazole (TMP-SMX).18 Howev- Also, the majority of organisms cultured in this study er, because the prevalence of resistance to TMP-SMX (E. coli, Enterococcus spp.) could be regarded as fecal among uropathogens is increasing, fluoroquinolones, microbiota, and the relatively short, wide urethra in with their low rate of adverse effects, convenient female cats is less likely to provide physical resistance to pharmacokinetics, and effectiveness, are increasingly the retrograde passage of fecal bacteria than is the being used as first-line drugs for the management of longer, narrower male urethra. cystitis.18 Prudent use of fluoroquinolones for the

Fig 1. Box and whisker plots of post-trial palatability scores for antimicrobial agents (Pradofloxacin—light gray box; Doxycycline—dark gray box; Amoxicillin/clavu/anic acid—clear box). Question 1 (left) and Question 2 (right). See text for scoring of questions. 994 Lister et al treatment of UTI is recommended, particularly because MPC of 7 veterinary fluoroquinolones tested for both E. increased use of these drugs for the treatment of UTI coli and Staphylococcus aureus isolates, and concluded and other infectious processes has resulted in an that, with appropriate dosing, pradofloxacin may increasing prevalence of fluoroquinolone resistance in combine high therapeutic efficacy with an unprecedent- uropathogens worldwide. This is especially true for E. ed potential for restricting the emergence of fluoroqui- coli isolates, where fluoroquinolone resistance is in- nolone resistance during therapy.22 creasingly associated with a multidrug-resistant (MDR) There is an emerging need for palatable oral phenotype.18,19 We have previously documented the pharmaceutical formulations for companion animals, emergence and spread of MDREC showing both and this factor has a major impact on issues such as fluoroquinolone and 3rd generation cephalosporin re- owner convenience and compliance, particularly for sistance in a veterinary teaching hospital.20,21 The chronically administered medications.25 All 3 antimicro- majority of these however were isolated from UTI in bials tested performed equally well, and none of the dogs, and MDREC appears to be quite rare in cats.22 participating owners reported inability to medicate their Interestingly, the single MDREC isolate reported in the cat during the trial. This observation reinforces the current study was 1 of 4 isolates obtained from a cat concept that there is a market for oral medications that that successfully responded to the trial treatment (ie, consider the needs of the cat and its owner, as well as amoxicillin-clavulanic acid). therapeutic efficacy and safety. Regarding the safety In a previous study, we identified Enterococcus spp. of pradofloxacin, although there were no adverse as the second most prevalent urinary tract pathogen in ophthalmologic effects observed in this study, the cats, with E. coli the most prevalent.10 In vitro studies long-term ocular safety of this drug in cats has not been have demonstrated that Enterococcus spp. often show evaluated. reduced susceptibility to older generation fluoroquino- We conclude that pradofloxacin 2.5% oral suspension lones in both humans and animals.23 Therefore, fluor- is a highly effective antimicrobial treatment for bacterial oquinolones would not routinely be recommended for lower UTI in cats, and that the palatable formulation treatment of UTI caused by these bacteria. Pradoflox- optimizes owner compliance. acin has a distinct advantage over earlier fluoroquino- lones in this respect, because it restricts bacterial selection for fluoroquinolone resistance under in vitro Acknowledgment conditions22 by simultaneously targeting both bacterial enzymes involved in DNA supercoiling (DNA gyrase Support for this study was provided by Bayer Animal and topoisomerase IV) in both Gram-negative and Health, Leverkusen, Germany. Gram-positive bacteria.23 Minimum inhibitory concen- tration (MIC) testing of a larger collection of urinary References tract isolates from Australian cats confirmed the 1. Buffington C, Westrop J, Chew D, et al. Risk factors superior activity of pradofloxacin against Enterococcus associated with clinical signs of lower urinary tract disease in when compared to older generation fluoroquinolones, indoor-housed cats. J Am Vet Med Assoc 2006;228:722–725. with an MIC90 value of 1 mg/mL as compared to 4 mg/ 2. 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Bactericidal prevent selection of first-step resistant variants naturally mechanisms of pradofloxacin, a novel 8-cyanofluoroquinolone. present in large bacterial populations.22 Such mutants 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology. San Diego, may be amplified by consecutive steps of clonal CA; 2002. enrichment under selective drug pressure during thera- 10. Litster A, Moss SM, Honnery M, et al. Prevalence of 22 py. The molecular structure of pradofloxacin restricts bacterial species in cats with clinical signs of lower urinary tract bacterial selection for antimicrobial resistance. A recent disease: Recognition of Staphylococcus felis as a possible feline study demonstrated that pradofloxacin had the lowest urinary tract pathogen. Vet Micro. 2007;121:182–188. Pradofloxacin for Urinary Tract Infection in Cats 995

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