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Original Article Comparison of the clinical efficacy of cefquinome with the combination of penicillin G and in equine patients A. Widmer*, M. Kummer, M. Wehrli Eser† and A. Fürst Equine Department Vetsuisse - Faculty Zurich, Section Surgery; and †Section Medicine, University of Zurich, Winterthurerstr. 260, CH-8057 Zurich, Switzerland.

Keywords: horse; cefquinome; treatment; cephalosporins

Summary dihydrothiazine ring. The differences among cephalosporin derivatives in antimicrobial activity, stability This prospective, randomised, nonblinded study against β-lactamases, protein binding, intestinal compared the clinical efficacy of cefquinome to that of a absorption, metabolism and toxicity are the result of the combination of penicillin and gentamicin. Patients presence of different groups at the R position (Vaden and (374 horses and 13 donkeys) at the equine hospital of the Riviere 2001). Vetsuisse-Faculty of Zurich, presented from February– The division of cephalosporins into 4 generations is October 2007, were divided into prophylactic and largely based on the time of introduction of the specific therapeutic treatment groups. Equids from these groups cephalosporin, although some generalities can be made were randomly treated either with cefquinome or with the for each group regarding their spectrum and combination of sodium penicillin and gentamicin. pharmacological behaviour. In general, first-generation There was no significant difference between the cephalosporins are effective against Gram-positive 2 treatment groups for prophylactic indications. In the organisms. Their spectrum is similar to that of therapeutic group, cefquinome showed better efficacy, as aminopenicillins. Second-generation cephalosporins are demonstrated by fewer complications of wound healing active against the same bacteria as first-generation and fewer treatment failures with subsequent change to cephalosporins, but their spectrum is extended to Gram- another antibiotic. Side effects were very rare in both negative bacteria. Third-generation cephalosporins are treatment groups. Cefquinome can be used with safety known to be less active against Gram-positive cocci, but and efficacy in equids. Cefquinome had greater efficacy have a wider range of activity against Gram-negative than the combination of penicillin and gentamicin in the pathogens than other cephalosporins. Some of them also therapeutic group. However, there was no difference have good activity against anaerobic bacteria (Vaden between the 2 antibiotic treatments in the prophylactic and Riviere 2001). Ceftiofur is a commonly used third- group. In order to minimise the development of resistance, generation cephalosporin. It shows good activity against cefquinome should therefore not be used for routine Gram-positive and Gram-negative anaerobes, including prophylactic treatment. Enterobacteriaceae, and against many anaerobes such as Clostridium spp. and Fusobacterium spp. (Yancey et al. Introduction 1987; Samitz et al. 1996). It should be administered by the i.m. route (Haggett and Wilson 2008). This fact makes Since the discovery of penicillin in 1928, many ceftiofur less suitable for perioperative prophylaxis. In have been developed. The first cephalosporin, horses that are treated for several days, administration of ‘cephalosporin C’, was isolated in 1945, and was derived antibiotics through an indwelling venous catheter is also from a fungus (Cephalosporium acremonium). All other preferred over i.m. administration. The side effects of cephalosporins are semi-synthetic derivatives of this ceftiofur are diarrhoea and colitis after high dosages, as cephalosporin C. Cephalosporins have the same basic well as minor irritation at the injection site (Mahrt 1992). composition, which contains a β-lactam ring and a Two cases of fatal enteritis have been seen after i.v. administration of ceftiofur in horses (A. Fürst, unpublished *Author to whom correspondence should be addressed. report). The occurrence of antimicrobial resistance EVE 08-131 Widmer:Layout 1 10/07/2009 16:22 Page 3

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against ceftiofur in equine pathogens has been reported concentration-dependent manner (Riviere and Spoo (Vo et al. 2007). Most of the isolates (Escherichia coli and 2001). There are few published reports of side effects Klebsiella pneumoniae) were resistant to multiple following administration of cephalosporins to horses in antibiotics (Vo et al. 2007). clinical situations. Anecdotally, however, there are The fourth-generation cephalosporins have a wider concerns about gastrointestinal tract disturbances spectrum than all other cephalosporins (Hornish and (gastrointestinal discomfort, anorexia, diarrhoea) (Mahrt Kotarski 2002). Cefepime, a cephalosporin of the fourth 1992; Guglick et al. 1998). generation that is used in human medicine, has been Antibiotics are used in man and domestic animals for shown to be active against most clinically important Gram- the treatment of and also for prophylactic positive and Gram-negative organisms and it is resistant to indications to prevent infections. The therapeutic use of hydrolysis by β-lactamases (Holloway and Palmer 1996). antibiotics is not questioned, because antibiotics are, in However, methicillin-resistant Staphylococcus aureus combination with surgical techniques, of great (MRSA) and multi-resistant Entercoccus should be importance in treating infections. It is important to select considered intrinsically resistant (Sood et al. 2008). an appropriate antibiotic in order to combat the Cefquinome is a cephalosporin of the fourth effectively, as well as to reduce the prevalence of generation that is used only in veterinary medicine. It has resistance. New antibiotics, such as cefquinome, have zwitterionic characteristics, which allow rapid been developed in an attempt to find an antibiotic with penetration of the Gram-negative outer membrane better efficacy against multi-resistant pathogens. (Murphy et al. 1994). Cefquinome has been found to be However, antimicrobial resistance develops fast, and effective against most major equine pathogens, prudent use of antimicrobials is the only way to combat including Staphylococcus spp., Streptococcus spp., the development of multi-resistant pathogens. Guidelines Actinobacillus equuli, enterobacteriaceae and for the prudent use of antibiotics are available elsewhere pasteurellaceae. In an in vitro study, it was less effective (Traub-Dargatz and Dargatz 2009). against Clostridium perfringens and Rhodococcus equi The aim of this study was to compare the clinical (Thomas et al. 2006). Cefquinome showed more limited in efficacy of cefquinome with a combination of penicillin vitro activity against Gram-negative and Gram-positive and gentamicin for therapeutic as well as for prophylactic anaerobic pathogens (Limbert et al. 1991; Murphy et al. use. 1994). The same in vitro study showed that cefquinome was more stable than other cephalosporins against Materials and methods β-lactamase (Limbert et al. 1991). In a study involving treatment of bovine mastitis, cefquinome showed good Patients presented to the equine hospital of the Vetsuisse- activity against Streptococcus spp., Staphylococcus spp. Faculty of Zurich from the beginning of February until the and enterobacteriaceae. Enterococcus spp. and end of October 2007 were divided into a prophylactic and Pseudomonas spp. were less susceptible (Shpigel et al. a therapeutic treatment group. These 2 groups were then 1997). Another clinical study showed that cefquinome split into groups representing different diagnoses. The also was efficient for the treatment of foals with therapeutic treatment group was divided into cases of septicaemia (Rohdich et al. 2007). peritonitis, respiratory tract infection, alveolar periostitis, Like that of other β-lactam antibiotics (e.g. penicillin), orthopaedic infections and infected soft tissue injuries the activity of cefquinome is time rather than (Table 1). The prophylactic treatment group comprised concentration dependent (Thomas et al. 2006). In patients undergoing colic surgery, colic patients without contrast, aminoglycosides, such as gentamicin, act in a surgery (e.g. caecal puncture), patients with noninfected

TABLE 1: Patient groups

Total number Indication Patient group Percentage (n = 387)

Therapeutic group Orthopaedic infections 11.9 46 Infected soft tissue injuries 17.3 65 Alveolar periostitis 4.4 17 Respiratory infections 2.8 11 Peritonitis 0.5 2 Prophylactic group Different elective surgeries (neurectomies, annular ligament 19.9 77 desmotomies, open castrations) Sterile closed castrations 10.6 41 Noninfected soft tissue injuries 9.6 37 Arthroscopies 9.3 36 Colic surgeries 7 27 Closed fractures 3.6 14 Colic patients without surgery (e.g. caecal puncture) 3.1 12 EVE 08-131 Widmer:Layout 1 10/07/2009 16:22 Page 4

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soft tissue injuries, those undergoing arthroscopies, sterile nasal discharge, enlarged submandibular lymph nodes, closed castrations, different elective surgeries, and those cough, as well as evaluation of the surgery site or wound with closed fractures (Table 1). For each group of diseases and the ability to bear weight (good, fair, poor), as (e.g. colic surgery) we created a randomisation list using appropriate, according to a scoring system (Table 2). Any Microsoft Excel1. Each new patient was given a continuous change to another antibiotic, because of treatment number in the specific disease list, which was assigned to failure (no improvement of the infection) or resistance to A or B for the prophylactic group, or to C or D for the the antibiotic during routine screening, was also noted. therapeutic group. Culture and antimicrobial sensitivity testing was performed In the prophylactic treatment group, horses were in cases of infection. treated either with cefquinome (Cobactan 4.5%)2 (Group A) at 1 mg/kg bwt q. 12 h i.v. or with a combination Statistics of penicillin (Penicillin G)3 at 30,000 iu/kg bwt q. 12 h i.v. and gentamicin (Vetagent)4 at 7 mg/kg bwt q. 24 h i.v. Daily observations were combined to form one score (yes (Group B). Perioperative prophylactic antibiotic treatment or no) for each parameter of interest (development of consisted of a single preoperative administration of infection and side effects). The parameters recorded cefquinome (Group A) or a preoperative administration of were: development of , development of the combination of penicillin and gentamicin with thrombophlebitis, occurrence of diarrhoea, occurrence of repeated administration of penicillin 6 h post operatively infection in the surgical site or wound, and delayed wound (Group B). Antibiotics were administered for 3 days in healing in the therapeutic group on any day during the patients with fresh injuries without open synovial cavities, observation period. and for 5–7 days in patients with open synovial cavities or A Chi-squared test was used for categorical variables closed fractures with internal fixation. Horses that and the independent sample t test for continuous underwent colic surgery were routinely treated for 5 days, variables. The statistical analyses were performed with if no complication occurred. SPSS, version 166. The significance level was set at P<0.05. Patients in the therapeutic treatment group were Power analysis was performed with STATA7 separately treated either with cefquinome (Group C) or with the for the prophylactic and the therapeutic treatment combination of penicillin (Group D), using the same doses groups. Alpha was set at 0.05 and beta at 0.2. In the as Groups A and B, respectively. Parallel to systemic prophylactic group an 8% reduction in the infection rate treatment with either cefquinome or the combination of was estimated. In the therapeutic group, a 15% increase in penicillin and gentamicin, equids with synovial infection or the cure rate was estimated. open synovial cavities were treated with intrasynovial injection of 150 mg cefquinome (Group C) or 250 mg Results amikacin sulphate (Amikin)5 (Group D). Patients were observed from the start until the end of There were 433 equids included in the study. Of these, 387 antibiotic treatment. Patients receiving only perioperative (374 horses and 13 donkeys) were included in the statistical antibiotics were observed until they left the hospital. evaluation. Thirty-three horses were excluded because of Daily observations included rectal temperature (fever missing data, or complications not related to antibiotic ≥38.4°C), occurrence of thrombophlebitis, diarrhoea, treatment, and 13 horses were subjected to euthanasia

TABLE 2: Scoring system

Parameter Score Definition

Fever Yes ≥38.4°C No Thrombophlebitis Yes Signs of inflammation at the catheter site (swelling, heat, pain) No Diarrhoea Yes Several episodes of soft manure No Surgical site infection Yes Signs of infection at the surgical site (swelling, draining, heat, pain) No Wound healing 0 = healing Healing: decreased signs of inflammation and infection (swelling, draining, heat, pain) 1 = stationary Stationary: no different from the day before 2 = worsening Worsening: increased inflammation and infection Weightbearing 0 = good Good: no lameness at walk 1 = fair Fair: mild lameness at walk 2 = poor Poor: moderate to severe lameness at walk Change of antibiotic Yes Antibiotics were changed: No - no improvement of infection after 3 days of treatment - continuous fever despite antimicrobial therapy - resistant pathogens after culture and sensitivity testing EVE 08-131 Widmer:Layout 1 10/07/2009 16:22 Page 5

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TABLE 3: Statistics for the prophylactic group: total number of TABLE 4: Statistics for the therapeutic group: total number of horses horses and percentages; P value of Chi-squared test and percentages; P value of Chi-squared test

Group B Group D Total Group A (penicillin/ P Total Group C (penicillin/ P Parameter number (cefquinome) gentamicin) value Parameter number (cefquinome) gentamicin) value

Total number of 246 128 118 Total number of 141 69 72 horses horses Development of 15 (6.1%) 8 (6.2%) 7 (5.9%) 0.98 Development of 6 (4.8%) 1 (1.6%) 5 (9.8%) 0.20 fever (≥38.4°C) fever (≥38.4°C) Development of 1 (0.4%) 1 (0.8%) 0 0.34 Development of 1 (0.7%) 0 1 (1.4%) 0.32 thrombophlebitis thrombophlebitis Occurrence of 1 (0.4%) 1 (0.8%) 0 0.34 Occurrence of 1 (0.7%) 1 (1.4%) 0 0.30 diarrhoea diarrhoea Surgical site/wound 11 (4.5%) 5 (3.9%) 6 (5.1%) 0.64 Complications in 9 (8.0%) 1 (2.0%) 8 (12.7%) 0.04 infection wound healing Change of antibiotic 11 (4.5%) 5 (3.9%) 6 (5.1%) 0.66 Change of antibiotic 7 (5.0%) 0 7 (9.7%) 0.008 treatment treatment

because of problems unrelated to antibiotic treatment; total, 1.6% of the patients (one horse) treated with 374 equids were discharged from the clinic. Thirteen had cefquinome developed fever despite antibiotic therapy, to be subjected to euthanasia during hospitalisation: compared with 9.8% of the patients (5 horses) treated with 2 because of contralateral limb laminitis; 2 because of the combination of penicillin and gentamicin. One horse recurrent colic after colic surgery; 2 with malignant developed thrombophlebitis (Group D) and one horse tumours on the head; 4 because of implant failure in diarrhoea (Group C). Nine out of 114 patients showed fracture treatment; 2 because of severe osteomyelitis; and delayed wound healing. There was a significant difference one horse because of a chronic synovial fistula after (P = 0.04) between Groups C and D, with Group C annular ligament desmotomy. (cefquinome) having fewer complications of wound The homogeneity of treatment groups was tested with healing than patients from Group D. There was also a the Chi-squared test for categorical variables and the significant difference (P = 0.008) between Groups C and D independent sample t test for continuous variables. There for the change of antibiotic treatment because of were no significant differences between patients in the treatment failure (0 horses from Group C and 7 horses from prophylactic or therapeutic treatment group nor between Group D). This means that there was a clinical cure rate of the 2 antibiotic groups with respect to age (P = 0.91), sex 100% for Group C and 90% for Group D. The power of the (P = 0.30) or breed (P = 0.32). Patients also had the same study was 79% for the therapeutic group. number of treatment days in the prophylactic (mean ± s.d. The other observed parameters (nasal discharge, 3 ± 3.14 days; P = 0.50) and the therapeutic treatment enlarged submandibular lymph nodes, cough) could not group (7 ± 3.6 days; P = 0.33), respectively. The mean age be analysed statistically, because the prevalence of the was 8.7 years, with a range of 1–29 years. The percentages clinical signs was too low. of patients in each category are shown in Table 1. Most of Positive bacterial cultures and antimicrobial sensitivity the horses were Warmblood horses (56%); the rest were tests could also not be evaluated statistically because of Thoroughbreds, Arabians, coldbloods, ponies and others. the low number of positive cultures. There were 246 equids treated with antibiotics for prophylactic indications (Table 3). In this group, 15/162 Discussion patients (6%) developed fever (≥38.4°C) under antibiotic therapy. One horse developed thrombophlebitis and one This study showed that cefquinome can be used in horses horse had diarrhoea. Both of these horses were treated safely and with very good efficacy. There were very few with cefquinome. Infection of the surgical site or wound side effects in either antibiotic treatment group. Side was noted in 11 patients (4.5%). The prevalence of surgical effects of antibiotic treatment include diarrhoea site infection in cases undergoing elective surgery and associated with a change in bacterial intestinal flora and those with fresh injuries was only 2.9%. an overgrowth of bacteria such as Clostridium difficile The antibiotic treatment was changed in 11 patients (Hird et al. 1986; Baverud et al. 1997; Gustafsson et al. (4.5%) because of treatment failure. Using the Chi-squared 1997; Owens et al. 2008). In man, cephalosporins have test, no significant differences were found for any of the been associated with Clostridium difficile diarrhoea parameters between the 2 groups receiving antibiotic (Owens et al. 2008). Other side effects of aminoglycosides treatment for prophylactic indications. The power of the such as gentamicin include oto- and nephrotoxicity study was 76% for the prophylactic group. (Riviere and Spoo 2001), especially in compromised and Therapeutic treatment was given to 141 equids (Table 4). dehydrated animals. There were no significant differences Of these, 6 developed fever despite antibiotic therapy. In between the 2 antibiotic treatments in the prophylactic EVE 08-131 Widmer:Layout 1 10/07/2009 16:22 Page 6

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group for any parameter. Therefore it would be Earlier studies showed that cefquinome is effective against reasonable to continue to use the standard treatment most of these pathogens in vitro (Thomas et al. 2006). (penicillin/gentamicin) for prophylactic indications in the However, it has to be emphasised that there are regional clinic (e.g. perioperative administration of antibiotics). differences in pathogens and their antimicrobial Cefquinome could be kept as a reserve antibiotic for resistance patterns. For example, MRSA was not found in a therapeutic use, because it is known that frequent use of study in Switzerland (Schnellmann et al. 2006), but is an a specific antibiotic leads to increased resistance (Levy emerging problem in Canada (Weese 2004, 2007; Weese 1982). In particular, cephalosporins have been shown to et al. 2005). Other common resistances also seem to be have great potential to promote selection of multidrug less frequent in Switzerland than in other countries (Wissing resistance (Dunowska et al. 2006). Resistance genes can et al. 2001). be transferred from domestic animal pathogens to Marsh and Palmer (2001) assessed bacterial isolates human pathogens and vice versa (O'Mahony et al. 2005; obtained from critically ill foals and tested their Weese et al. 2006; Vo et al. 2007), which highlights the antimicrobial susceptibility. Escherichia coli was the most importance of the prudent use of antimicrobials in man as commonly isolated pathogen; other isolates included well as in other animals. Although not yet a problem in Klebisella spp., Salmonella spp., Enterobacter spp., horses in Europe, methicillin-resistant Staphylococcus Actinobacillus spp., Pseudomonas spp., Acinetobacter aureus (MRSA) and other multi-resistant pathogens, such spp., Streptococcus spp. and Staphylococcus spp., as well as vancomycin-resistant Enterococcus (VRE), will as Enterococcus spp. In general, susceptibility was highest probably be isolated more frequently in the future for amikacin (90%) and was good (80%) for ceftiofur and (Schnellmann et al. 2006). gentamicin (Marsh and Palmer 2001). Cefquinome, as a Equids undergoing elective surgery are usually free of fourth-generation cephalosporin, should have even better infectious disease and not pretreated with antibiotics. In efficacy than ceftiofur (a third-generation cephalosporin) these cases, the combination of penicillin and gentamicin against these pathogens. Ceftiofur is commonly used to seems to be a good prophylactic antibiotic treatment. The treat horses, especially for respiratory infections (Folz et al. power analysis gave a value of only 76% for the estimation 1992; Dyke and Hinchcliff 1993). Its disadvantage is the of an 8% reduction in the infection rate in the prophylactic need for intramuscular administration. Marsh and Palmer group when using cefquinome instead of penicillin and (2001) recommended broad-spectrum antibiotic therapy gentamicin. A 10% infection rate was estimated for for critically ill foals. penicillin and gentamicin when elective surgeries and Another indication for antimicrobial therapy is other surgeries (such as celiotomy) were combined. bacterial respiratory disease. Bacteria isolated from such However, in our study, the overall infection rate was only cases include Streptococcus spp., Staphylococcus spp., 4.5%. Therefore a much larger sample size would have Actinobacillus spp., Acinetobacter spp., Corynebacterium been needed to demonstrate a significant difference spp., Klebsiella pneumoniae, Pseudomonas aeruginosa between the 2 treatment regimes. and Mycoplasma spp. (Wood et al. 2005). Again, in vitro In the therapeutic group, cefquinome was associated studies showed good activity of cefquinome against these with fewer complications of wound healing and had less pathogens (Limbert et al. 1991; Thomas et al. 2006). often to be exchanged with another antibiotic because of Therefore cefquinome can be recommended for foal treatment failure. Equids in the therapeutic group were septicaemia and respiratory disease, as well as for referred to the hospital with pre-existing infections, and orthopaedic infections. had often been pretreated by the local veterinarian. Only In our study, we gave cefquinome every 12 h, except severe cases, probably infections with more resistant for perioperative use when it was given every 24 h. The pathogens, were referred to the clinic. This is a limitation of reason was to simplify application in a clinic with several the study. We could not control for antibiotic pretreatment veterinarians, and also because of fear of the by the local veterinarian. Therefore some patients were development of resistant hospital pathogens. not pretreated and some patients were reported to have In conclusion, cefquinome can be administered with been pretreated with different antibiotics (penicillin/ safety and efficacy to equids. It can be used as an gentamicin, cefquinome, marbofloxacin, trimethoprim/ alternative to the combination of penicillin and sulphonamide and enrofloxacin). gentamicin. Cefquinome shows better results in treating Initial treatment of an infection must be based on established infections than the combination of penicillin consideration of the most probable pathogens, until the and gentamicin. results of culture and an antibiogram become available. Pathogens known to be involved in orthopaedic infections Acknowledgements include enterobacteriaceae (Escherichia coli, Proteus spp., Enterobacter spp., Klebsiella spp.), Streptococcus We are grateful to Intervet-Schering-Plough International spp., Staphylococcus spp., Pseudomonas spp., obligate for supporting the funding of this study. We are thankful to anaerobes and Actinobacillus spp. (Snyder et al. 1987). the reviewers for their help with the manuscript. EVE 08-131 Widmer:Layout 1 10/07/2009 16:22 Page 7

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Manufacturers’ addresses Owens, R.C., Jr., Donskey, C.J., Gaynes, R.P., Loo, V.G. and Muto, C.A. (2008) Antimicrobial-associated risk factors for Clostridium difficile infection. Clin. Infect. Dis. 46 Suppl. 1, S19-31. 1Microsoft, Seattle, Washington, USA. 2Intervet Schering-Plough, International, Boxmeer, The Netherlands. Riviere, J.E. and Spoo, J.W. (2001) Aminoglycoside antibiotics. In: 3Streuli Pharma, Uznach, Switzerland. Veterinary Pharmacology and Therapeutics, 8th edn., Ed: H.R. 4Veterinaria Ltd, Zürich, Switzerland. Adams, Iowa State University Press, Ames. pp 841-861. 5 Bristol-Myers Squibb, Baar, Switzerland. Rohdich, N., Zschiesche, E. and Heckeroth, A. (2007) Treatment of 6 SPSS Schweiz AG, Zürich, Switzerland. septicemia and severe bacterial infections in foals with a new 7 Stata, College Station, Texas, USA. cefquinome formulation (Cobactan IV 4.5%): a field study. In: Veterinary European Equine Meeting of the Year 2007, Bologna. 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