Antimicrobial use for selected diseases in cats in Switzerland

Background Antibiotic use in human and veterinary medicine is considered a main driver of antimicrobial resistance. Although guidelines to promote appropriate use of antimicrobials in veterinary patients have been developed, antibiotic overprescription is assumed to be a common problem. The goal of this study was to investigate antimicrobial use in cats in Switzerland with acute upper respiratory tract disease (aURTD), feline lower urinary tract disease (FLUTD) and abscesses, and to assess compliance of prescription with consensus guidelines. A total of 776 cases (aURTD, n = 227; FLUTD, n = 333; abscesses, n = 216) presented to two university hospitals and 14 private veterinary practices in Switzerland during 2016 were retrospectively evaluated. Clinical history, diagnostic work-up and antimicrobial prescription (class, dosage, duration) were assessed. Results A total of 77% (aURTD), 60% (FLUTD) and 96% (abscesses) of the cases received antibiotic therapy; 13–24% received combination or serial therapy. The cats were treated for a median of 7 (abscesses) and 10 days (aURTD, FLUTD). Treatments with potentiated aminopenicillins (40–64%), third generation cephalosporins (25–28%), aminopenicillins (12–24%) and fluoroquinolones (3–13%) were most common. Prescriptions were judged in complete accordance with consensus guidelines in 22% (aURTD), 24% (FLUTD) and 17% (abscesses) of the cases. Antibiotics were prescribed although not indicated in 34% (aURTD), 14% (FLUTD) and 29% (abscesses) of the cases. The presence of lethargy, anorexia or fever in cats with aURTD, and the detection of bacteriuria in cats with FLUTD were significantly associated with antibiotic therapy. Although diagnostic work-up was significantly more common (aURTD: university hospitals, 58%; private practices, 1%; FLUTD: university hospitals, 92%; private practices, 27%) and the use of critically important antibiotics significantly less common at the university hospitals (aURTD, 10%; FLUTD, 14%) compared to private practices (aURTD, 38%; FLUTD, 54%), the frequency of antibiotic treatment was not different between the university hospitals and private practices. Conclusions Our results indicate that overprescription of antibiotics in cats in Switzerland is common and accordance with guidelines is poor. The study highlights the need to promote antimicrobial stewardship in small animal medicine.


Background
Mitigation of antimicrobial resistance has been an emerging topic that plays an important role in human and veterinary medicine. Antimicrobial resistance in bacteria is a naturally occurring phenomenon and has been subject to evolution over millions of years [1][2][3][4][5]. The frequent use of antimicrobials in human and veterinary medicine and in agriculture exerts an enormous selection pressure on bacterial populations and promotes the development of multidrug-resistant bacteria that can readily spread their resistance genes by various mechanisms [1][2][3]. Antibiotic use in veterinary medicine is discussed as one of the main drivers for resistance development. In Europe, around 8000 tons of antibiotics were sold for veterinary use in 2015, with pronounced differences between countries [6]. The amount of antibiotics used in companion animals in Europe in comparison to the amount prescribed in livestock is relatively small [6], but is not to be neglected. The close contact of pets with their owners facilitates the transmission of multidrug-resistant organisms between humans and companion animals [1,[7][8][9][10][11][12][13][14]. Furthermore, the trend for intensive medical care of dogs and cats poses a risk for nosocomial infections [15][16][17][18] and is associated with an increasing number of geriatric and immunosuppressed patients that are highly susceptible to infections with multidrug-resistant bacteria.
The aims of this study were to investigate the antimicrobial prescribing practice in Switzerland for indications in cats with frequent use of antibiotics, i.e., in cases of acute upper respiratory tract disease (aURTD), feline lower urinary tract disease (FLUTD) as well as abscesses, and to evaluate to what extend the prescriptions comply with recently established consensus guidelines [40,41]. The a priori compliance with the proposed guidelines was evaluated in this study to lay the basis to monitor, in a next step, the impact of these guidelines on antimicrobial prescription patterns in Switzerland.

Antibiotic prescription for aURTD
Of 227 cats with aURTD, 175 (77%) received antibiotic therapy with the following substance classes: potentiated aminopenicillins (40%), third generation cephalosporins (28%), aminopenicillins (24%), tetracyclines (16%), fluoroquinolones (4%), amphenicols (2%), macrolides (2%), first generation cephalosporins and penicillins (1% each); 15% of the cases received combination or serial therapy. The antimicrobial combinations used were potentiated or non-potentiated aminopenicillins together with fluoroquinolones, first generation cephalosporins, tetracyclines, amphenicols or third generation cephalosporins. One cat received a triple therapy consisting of an aminopenicillin, a fluoroquinolone and a tetracycline. The cats were treated for 4 to 37 days (median of 10 days). Antibiotic therapy was significantly associated with the indications listed in the guidelines (presence of lethargy, anorexia or fever, p = 0.002). The treatment decision was judged as being compliant with the guidelines (justification score-1, JS-1) in 49 cases (22%) and not in accordance with the guidelines in 135 cases (59%; JS-2: n = 4, 2%; JS-3: n = 48, 21%; JS-4, n = 83, 36%). In the 83 cases where a complete discrepancy with the guidelines was found (JS-4), antibiotic prescription although not indicated (overprescription) occurred in 78 cases (94%) whereas 5 cases (6%) did not receive antibiotics despite indicated in the guidelines. The lack of information on the presence or absence of disease symptoms as listed in the guidelines precluded judgment in 43 cases (19%). Judgement of antimicrobial prescription was significantly more often not possible in private practices compared to the university hospitals (p = 0.001).
The diagnostic work-up and antimicrobial prescription patterns differed between private practices and university hospitals ( Table 2). The aURTD cases were significantly more frequently tested by PCR for the presence of respiratory pathogens at the university hospitals (58%) compared to private practices (1%). The choice of antibiotic was significantly more often in disagreement with the guidelines (JS-3) at the university hospitals (61%) than at the private practices (12%). This was mainly due to the more common use of potentiated aminopenicillins (university hospitals, 90%; private practices, 29%) and the less common use of aminopenicillins (university hospitals, 3%; private practices, 28%) at the university hospitals compared to private practices. On the other hand, the use of critically important antibiotics was significantly more common in private practices (38%; university hospitals, 10%). The decision to use antibiotics for  treatment was significantly more often in disagreement with the guidelines (JS-4) in the private practices (43%) when compared to the university hospitals (7%).

Antibiotic prescription for FLUTD
Of 333 cats with FLUTD, 200 cases (60%; 56 with bacterial cystitis, 144 with other/unknown diagnosis) received antibiotic therapy with the following substance classes: potentiated aminopenicillins (61%), third generation cephalosporins (26%), fluoroquinolones (13%), aminopenicillins (12%), first generation cephalosporins (3%), amphenicols (1%) and tetracyclines (1%); 13% received combination or serial therapy. For combination therapy, potentiated or non-potentiated aminopenicillins together with fluoroquinolones or third generation cephalosporins were used. The cats were treated for 1 to 56 days (median of 10 days). The presence of bacteriuria was significantly associated with antibiotic therapy (p < 0.001). The treatment decision was judged as being compliant with the guidelines (JS-1) in 81 (24%) and not in accordance with the guidelines in 82 (25%) cases (JS-2: n = 1, 1%; JS-3: n = 31, 9%; JS-4: n = 50, 15%). In the 50 cases with complete discrepancy to the guidelines (JS-4), antibiotics were prescribed although not indicated (overprescription) in 47 cases (94%) and cats were not treated with antibiotics despite indicated in the guidelines in 3 cases (6%). Inadequate diagnostic work-up (154 out of 170 cases, 91%) was the main reason to preclude judgment in 170 cases (51%). Diagnostic work-up and antimicrobial prescription patterns were again different between the university hospitals and private practices (Table 3). Urine sediment analysis or bacterial culture were significantly more commonly performed at the university hospitals (92%) compared to private practices (27%). When antimicrobial prescription at the university hospitals was compared to the private practices, prescription was significantly more often graded as JS-1 (complete agreement with the guidelines; university hospitals, 44%; private practices 12%), JS-3 (choice of antimicrobial different from the guidelines; university hospitals, 17%; private practices 4%) and JS-4 (complete discrepancy with the guidelines; university hospitals, 30%; private practices 6%). The use of critically important antibiotics was significantly more common in private practices (54%) compared to the university hospitals (14%). Furthermore, judgment of antimicrobial prescription was significantly more often not possible in private practices (78%; university hospitals, 8%).

Discussion
The results of this study indicate that overprescription of antibiotics in cats in Switzerland with aURTD, FLUTD and abscesses is very common. When prescription was compared to the consensus guidelines, 14-34% of all cases received antibiotics although not indicated; when only the cases were considered for which judgment of prudent use was possible, the rate of antibiotic overprescription was even higher (29-48%). The diagnostic work-up was more elaborate at the university hospitals, and critically important antibiotics were less commonly prescribed at the universities, but the prudent use pattern of prescriptions was not clearly superior when compared to private practices. This was mainly due to the very common use of potentiated aminopenicillins instead of non-potentiated Signs of generalization, poor general condition, severely contaminated wounds, and/ or proximity to delicate tissues; b Values for the category "no" (reference group) are not shown; c As defined in methods aminopenicillins at the universities. On the other hand, the quality of antimicrobial prescription could often not be judged in the cases from private practices because the diagnostic work-up or the symptoms of the patients were not documented. The common discrepancy of antimicrobial prescription with recently established consensus guidelines [40,41] at the two university hospitals is surprising considering that senior clinicians of these hospitals were involved in the drafting of the guidelines. The overall frequency of antimicrobial treatment was also not different at the university hospitals compared to private practices. However, our data indicates that the animals presented to the university hospitals were more often pretreated or hospitalized, and could thus have been in a more debilitated condition. Only 17 ̶ 24% of the treatment decisions in this study were classified as JS-1 and therefore in complete accordance with the consensus guidelines. Recent studies in dogs and cats have reported an overall agreement of 0-69% with published guidelines [24,27,33,34]. This overall low accordance raises the question of whether the proposed guidelines cannot be implemented in clinical practice, for example, due to poor market availability of appropriate antibiotic formulations, or whether the content is not well disseminated among veterinary practitioners.
The critically important antibiotics used in cats in this study were mostly third generation cephalosporins as well as fluoroquinolones. Third generation cephalosporins were the second most frequently prescribed antibiotic class and were used in 25-28% of the cases. This mirrors the results obtained in previous studies [21][22][23][24][25][31][32][33] and could likely be explained by the convenient application (as a single subcutaneous injection) and the long dosing interval (2 weeks) of the authorized product in Switzerland (cefovecin, Convenia®, Zoetis, Delémont, Switzerland). A previous study evaluating electronic health records found that inability to orally medicate the cat was the most common reason given for prescribing cefovecin [42]. An online survey in veterinarians in Switzerland also revealed that the route of application was the most important factor in the choice of antimicrobial therapy in cats [43]. In our study, the prescription of critically important antibiotics was significantly more frequent in private practices compared to the university hospitals. This observation supports the hypothesis that the workplace environment is an important factor determining treatment decisions and antimicrobial use [44]. University hospitals, as training centers, may have stronger restrictions for the use of critically important antibiotics: one of the two university hospitals of this study completely forbids the use of third generation cephalosporins in its patients. On the other hand, the cats at the university hospitals were more commonly hospitalized compared to the cases in private practices, thus allowing for parenteral medication and avoiding the problem of oral application of the antibiotic drug.
Antimicrobial prescription in the absence of proper diagnostic work-up was very common in this study. In only 40% of the FLUTD cases overall, and in only 10% of the FLUTD cases in private practices, bacterial culture and susceptibility testing were carried out. In a previous study based on a questionnaire, 32.5% of companion animal practitioners in Europe reported that they frequently undertake antimicrobial susceptibility testing whereas 9.1% never demand such tests [45]. In another survey from Italy, 91% of the practitioners reported to carry out microbiological analysis, although only 20% reported to do so frequently [35]. Our results indicate that these data based on questionnaires are probably too optimistic and that bacterial culture, an essential diagnostic work-up step for cats with FLUTD, is rarely performed in private practices. In contrast, bacterial culture was performed in 87% of the FLUTD cases presented to the university hospitals, although this did not result in a less frequent prescription of antimicrobials. Interestingly, 56% of the FLUTD cases at the universities received antibiotic therapy despite the absence of bacteria in urine culture. A total of 20% of these cats were pretreated with antibiotics which could have affected the interpretation of a negative bacterial culture result. Also many of these cats suffered from urinary tract obstruction and antibiotic therapy was initiated after removal of the indwelling urinary catheter.
The trend towards more diagnostic testing at the university hospitals is also demonstrated by a more frequent use of PCR for the detection of feline calicivirus (FCV) and feline herpesvirus-1 (FHV) in cases with aURTD. These tests can be useful to support a diagnosis of viral infection and to initiate supportive measures such as the prescription of famciclovir in the case of FHV infection, and thus reduce the use of antibiotics [46]. In this study, the detection of FCV and FHV did not affect the frequency of antibiotic prescription. Overprescription of antibiotics in cats with aURTD was common: although only 29% of the cats showed symptoms that would have justified an antibiotic therapy according to the consensus guidelines, 77% of the cases received antibiotic treatment. Potentiated aminopenicillins were most often prescribed at the university hospitals, while third generation cephalosporins and aminopenicillins were most commonly used in private practices. A study revealed that amoxicillin with clavulanic acid is not superior to doxycycline when treating cats with signs of acute respiratory tract disease [47]. Our data, however, indicate that the cases presented to the university hospitals were in a more debilitated condition, because 72% of the cats with aURTD were hospitalized in comparison to 3% in private practices. Furthermore, 68% of the cats presented to university hospitals had symptoms listed in the guidelines, while at the private practices only 21% of the cats were reported to show a poor general condition, fever, lethargy and/or anorexia. The more compromised clinical condition of the patients at university hospitals could explain the common use of potentiated aminopenicillins instead of doxycycline due to the lack of a licensed injectable doxycycline preparation in Switzerland. However, potentiated instead of non-potentiated aminopenicillins were almost exclusively used at the universities. Non-potentiated and potentiated aminopenicillins are often used interchangeably although it has been shown that the use of clavulanic acid may increase AmpC-mediated resistance causing inducible organisms to become insensitive to 1st to 3rd generation cephalosporins [48,49]. The frequent use of potentiated aminopenicillins instead of non-potentiated aminopenicillins in this study could also be due to the better availability of these products on the market, since they make up the largest part of antimicrobial compounds licensed for cats in Switzerland [50].
A total of 96% of the cats with abscesses received antibiotic treatment but only 30% of the cats presented symptoms that, according to the guidelines, would justify an antibiotic therapy. Our findings are in line with results from previous studies where frequency of antibiotic prescriptions for skin diseases such as wounds or abscesses ranged from 90 to 97% [24,32]. In children, antibiotics might sometimes be applied instead of local wound drainage to avoid anesthesia or sedation [51]. However, 72% of the cats in this study received local wound treatment and passive drains were placed in 15% of the cats. It can be assumed that, in many of these cases, antibiotics were supplemented as a preventative measure. Studies from human medicine showed that appropriate drainage of the abscess is important and that antibiotic treatment may not be necessary [52][53][54][55]. Several guidelines for small animals state that an antibiotic treatment is not indicated if the abscess is well-defined and the animal is in a good general condition [56][57][58].
The present study has some limitations. The insufficient documentation in the databases limited the information available for review. The presence of bacteria in urine sediment analysis of an aseptically collected urine sample was considered appropriate to confirm a bacterial etiology in cases with FLUTD, although this is considered insufficient diagnostic work-up according to some guidelines due to the variable quality of interpretation, the risk of stain contamination as well as the possibility of false positive results [57,59]. In a recent study, overall accuracy of in-house microscopic evaluation for bacteriuria in primary practice was only 64.5% when comparing results to reference bacterial cultures [60]. We decided to consider these results since former studies have reported accuracies of urine sediment analysis of 97-98% when performed by experienced laboratory personal [61][62][63][64]. Furthermore, the generally low prevalence of bacterial cystitis in cats should not result in many false positive results [65][66][67].
The assessment score used in this study leaves a margin of interpretation and the justification of antimicrobial prescription was based on consensus guidelines released in Switzerland. Results could differ to some extent when comparing prescription to guidelines from other countries. Furthermore, the limited number of cases included per practice did also not allow for a statistical analysis at a single practice level. Also, there could be a selection bias since the participation in this study was on a voluntary basis and the enrolled practices might have been more aware of antimicrobial resistance and more likely to prescribe antibiotics prudently.

Conclusions
The present study highlights the need to promote antimicrobial stewardship in small animal medicine and to implement effective intervention strategies. Particular attention should be paid to the education of veterinarians, the propagation of diagnostic work-up and the need for proper documentation to justify antibiotic treatment. Antimicrobial stewardship at universities should be urgently advanced as they serve as role models for veterinary practice. Developments on the market to provide small spectrum antibiotics for convenient application would be of particular importance in cats since the route of application is a major factor in the choice of antimicrobials in this species. Such new products will contribute to ensure that effective antimicrobials remain available in the future to combat bacterial infections in human and veterinary medicine.

Methods
Cases presented between January 1st and December 31st 2016 to the two Swiss university teaching hospitals for small animals (Vetsuisse Faculty Bern and Zurich) as well as to fourteen private veterinary practices across Switzerland were included. The private practices participated on a voluntary basis following a nationwide call. In order to identify patients matching the inclusion criteria (Table 5), the electronic records were scanned for predetermined search terms (Table  5) using search functions provided by the particular software. For practical reasons, only private practices using either OblonData® (Amacker&Partner Informatik AG, Zurich, Switzerland) or Diana SUISSE® (Diana Software AG, Zurich, Switzerland) were enrolled. A full text search was conducted and the matches were manually reviewed. All cases from the two university hospitals matching the criteria were included. From each private practice, 16 cases per indication that matched the criteria were randomly selected via the sampling function of Microsoft® Excel. In the eight private practices where less than 16 cases per indication were found, all cases were included. The number of cases was balanced by limiting the number to 16 per practice to avoid overrepresentation of larger private practices. Although not all cases were included, the random selection should ensure that the results remain representative.
Signalment, vaccination status, clinical history, reports on clinical examination, antibiotic pretreatment, diagnostic work-up, comorbidities, hospitalization and antimicrobial therapy (substance class, dose, frequency of application and duration of therapy) were retrieved from the medical records. The evaluated diagnostic work-up for aURTD included PCR for FCV and FHV; for FLUTD, urine sediment analysis and urine bacterial culture were assessed. Bacteriuria was defined as the presence of bacteria in the urine sediment analysis or in the bacterial culture from an aseptically collected urine sample (cystocentesis or catheterization). Complicated urinary tract infections were defined as infections that were caused by anatomical or functional changes or a comorbidity, that predispose the patient to persistent or recurrent infections or treatment failure [68]. Critically important antibiotics comprised third or higher generation cephalosporins, quinolones, macrolides, ketolides, glycopeptides and polymyxins [69]. Combination therapy was defined as the prescription of two or more antibiotic classes at the same time; serial therapy as the prescription of one antibiotic class followed by a different antibiotic class. Antimicrobial prescription was compared with the consensus guidelines summarized in Table 6 using a previously published JS with modifications shown in Table 7 [70]. The guidelines were published in December 2016 [40] and can be accessed online as the AntibioticScout tool [71]. The present study evaluated antimicrobial prescription prior to the implementation of the guidelines to use this data as a baseline for follow-up studies on the influence of the guidelines on antimicrobial prescription in Switzerland.
For statistical analysis, the commercially available SPSS® software (SPSS Inc., IL, USA) was used. Descriptive statistics and comparisons of groups were conducted. Because the continuous variables were not  work-up, hospitalization, antibiotic pretreatment and antibiotic prescription) between university hospitals and private practices; frequency of antibiotic therapy between the indications; association of symptoms listed in the guidelines (for aURTD and abscesses) or the presence of bacteriuria (for FLUTD) with antibiotic therapy. The level of significance was set at p < 0.05. For the comparison of the justification scores between university hospitals and private practices the Chi square test was performed and the significance level was adapted for multiple tests using the Bonferroni correction.   [70]; b A margin of 1 day shorter or longer was tolerated; c A deviation of up to 20% above or below the recommended dose was accepted; d Each case was scored only once. If the dose or duration of treatment as well as the antibiotic class were deviating from the guidelines, the case was categorized as JS-3