Zosyn: A Replacement for Pipracil in the Avian Patient
Presenting Author: Larry P. Nemetz, DVM
Co-Author: Angela Lennox, DVM, Dipl (Avian)
This is the exact manuscript submitted to AAV by Dr. Nemetz. References are left out to conserve space.
Affiliation: From The BIRD Clinic Veterinary Corporation, 2525 North Grand Ave, Suite R, Santa Ana, CA 92705, USA (Nemetz) and Avian and Exotic Animal Clinic, 9330 Waldemar Road, Indianapolis, IN 46268, USA (Lennox)
Abstract: Piperacillin sodium (Pipracil, Lederle Piperacillin, Inc., Carolina, Puerto Rico) was used in avian medicine with success due to its broad spectrum antibacterial properties. Since the discontinued production of piperacillin, ticarcillin has been suggested as its best alternative. Piperacillin sodium/tazobactam sodium injectable (Zosyn, Lederle Piperacillin, Inc., Carolina, Puerto Rico) was produced as a superior product with the addition of the beta-lactamase inhibitor tazobactam. Human studies have found Zosyn more effective than cephalosporins, aminoglycosides, quinolones or other penicillins alone or in combination with beta-lactamase inhibitors. Some strains of Pseudomonas aeruginosa have shown resistance requiring combination therapy with an aminoglycoside. Zosyn was approved in the United States for intravenous use only, but was approved for intramuscular use in countries outside the United States. Zosyn's easy availability, broad spectrum activity, and route of administration has made it an excellent substitute for Pipracil in avian medicine. Zosyn (200 mg/ml) has been used successfully in avian practice at 100 mg/kg IM q8-12h or 100 mg/kg IV q6h for severe polymicrobic bacteremia.
Key words: avian, antibiotic, piperacillin, tazobactam, beta-lactam, zosyn, pipracil
Introduction
Bacterial disease is a common diagnosis in avian medicine. A variety of pathogenic bacteria and opportunistic non-pathogens can cause disease in the avian patient. While antimicrobial selection should be guided by appropriate culture and sensitivity of the organism in question, Pipracil has often been a good choice due to excellent broad-spectrum activity.1
Pipracil was approved for intramuscular (IM) and intravenous (IV) use in human patients and has been used widely in avian medicine for years. Most exotic animal formularies list the avian dosage as 100 mg/kg to 200 mg/kg IM q8-12h. When diluted to the proper concentration, piperacillin sodium could safely be administered IV to avian patients.1 Some practitioners have reported rare sensitivity reactions to piperacillin sodium. Pipracil is no longer manufactured. Zosyn was evaluated as an equivalent or superior broad spectrum antibiotic for the replacement of Pipracil in avian medicine
Zosyn is an IV antibiotic combination product consisting of piperacillin sodium (a semisynthetic penicillin) and tazobactam sodium.2 A beta-lactamase inhibitor, tazobactam sodium, was added to piperacillin sodium to potentiate its activity against B-lactamase producing bacteria such as staphylococcus and some streptococcus. Zosyn was FDA approved for use in the United States in 1994.3 Zosyn is labeled in the United States for only IV use in human patients. It is reconstituted and administered slowly over 30 minutes. Once reconstituted, it is stable for 24 hours at room temperature, and 48 hours when refrigerated. While piperacillin/tazobactam has broad activity against gram-positive aerobic, gram-negative aerobic, and anaerobic bacteria, it is specifically indicated in humans for appendicitis and peritonitis, dermatitis, post-partum endometritis and certain types of bacterial pneumonia.2
Ticarcillin has been suggested in avian medicine as piperacillin sodium's best alternative.4 However, piperacillin/tazobactam has been shown in vitro and human clinical trials to be superior in overall antimicrobial activity against Enterobacteriaceae, Pseudomonas aeruginosa, Escherichia coli, Acinetobacter species, Staphylococcus aureus, and Klebsiella pneumoniae compared to ticarcillin/clavulanic acid, ampicillin/sulbactam, ceftazidime, ceftriaxone, cefotaxime, cefoxitin, aztreonam, imipenem, levofloxacin, amikacin, and vancomycin.5,6 Avian practitioners have combined piperacillin therapy with amikacin or other aminoglycosides in order to obtain a synergistic effect1. In vitro mixing of piperacillin/tazobactam with an aminoglycoside has been shown to cause substantial inactivation of the aminoglycoside.2 When added independently, recent in vitro studies demonstrated a synergistic effect of piperacillin/tazobactam and amikacin combinations (42%) and superiority to combinations with trovafloxacin (33%) and ciprofloxacin (8%) against Pseudomonas aeruginosa.7
Zosyn has been approved for IM q12h use in some European countries.8,9 The IM drug half-life of both piperacillin and tazobactam are much longer, approximately 20%, as compared to IV administration.8 In a prophylactic therapy study of piperacillin/tazobactam IM q12h versus ciprofloxacin PO q12h for patients undergoing transrectal prostatic biopsy, there was a lower incidence of pyrexia and positive urine cultures in the piperacillin/tazobactam group as compared to the ciprofloxacin group.9 Piperacillin sodium and tazobactam sodium were also shown to reach sufficient drug concentrations in cortical and cancellous bone to exert antimicrobial and anti-beta-lactamase activity in bone and joint pathology.10
Clinical Report
In an avian practice (The BIRD Clinic) from 2000 to 2004, Zosyn was used safely and effectively in more than 500 avian patients with good response and without recognizable adverse effects. Clinical use has included the treatment of the following conditions: bite wounds, bacterial celitis, severe self-mutilation, septicemia, and osteomyelitis. Zosyn was also used as the primary presurgical antibiotic in all orthopedic and abdominal procedures. Piperacillin/tazobactam was reconstituted to 200 mg/ml and administered routinely at the same dosage reported for piperacillin sodium (100 mg/kg IM q12h) or 100 mg/kg IV q6h for severe polymicrobic bacteremia. There was no apparent pain during injection and no recognizable pectoral bruising. Histopathology of muscle tissue from a budgerigar ( Melopsittacus undulatus) that received seven injections of piperacillin/tazobactam at 100 mg/kg IM demonstrated only rare areas of necrotic muscle fibers with fibroplasia and no active inflammation. Changes were characterized as mild to minimal.
Conclusion
The routine use of Zosyn in the avian patient at 100 mg/kg q8-12h IM, 100 mg/kg q6h IV for severe or polymicrobic bacterial infections, and 100 mg/kg q12h IM for preoperative orthopedic or coelomic surgery is not only a safe and effective replacement for Pipracil, but superior in antimicrobial activity due to the anti-beta-lactamase activity of tazobactam. This clinical report does not represent a properly conducted pharmacokinetic study or drug trial. However, empirically and supported by in vitro evaluation, human trials, and avian clinical experience, Zosyn has a broader therapeutic efficacy than piperacillin sodium alone as well as many antimicrobials presently used in avian medicine.
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