Do’s and don’ts of cephalosporin use in swine
An interview with
John W. Hallberg, DVM, PhD
Director, US Regulatory Affairs
Q: Cephalosporins have been key to successful management of respiratory disease in swine. However, they are medically important antimicrobials in human medicine, and FDA has understandably set limits on their use. Are there any issues you’re aware of regarding compliance with cephalosporin use throughout the pork industry?
JH: Swine producers and veterinarians have done a great job adhering to the rules regarding cephalosporin use in food animals. We do get questions from time to time, however, when certain situations lead to uncertainty about compliance, especially regarding extralabel (oﬀ-label) use.1
Q: Are there any situations when extralabel use of a cephalosporin is permitted?
JH: If you have a group of pigs with an illness due to a pathogen that’s not on the label and for which there’s no approved therapy — salmonellosis due to Salmonella, for example — using a cephalosporin would be justiﬁed. Another instance would be if an approved therapy has failed and it’s the veterinarian’s professional opinion that a cephalosporin may be eﬀective.
Q: Let’s say a group of young pigs is unthrifty but doesn’t have respiratory signs. If it can be documented in sacriﬁced pigs that Streptococcus suis is present, can they be treated with a cephalosporin?
JH: Yes, they can, as long as the veterinarian believes their poor health is likely due to S. suis.
Q: What about extralabel use of a cephalosporin for the prevention of a disease?
JH: Never. FDA deﬁnes prevention as treatment of a group of animals when none have clinical signs of disease or in a situation where a disease is likely to occur if the medication isn’t administered. Don’t do it.
Q: The labels for Naxcel® (ceftiofur sodium) and Excenel® RTU EZ (ceftiofur hydrochloride) say swine “should be treated for a total of 3 consecutive days.” What if unforeseen circumstances on the farm get in the way of following that exact protocol?
JH: Veterinarians and producers should make every eﬀort to be good antibiotic stewards and follow the recommendations on the product’s label. Those directions for use were deemed by FDA to be most safe and eﬀective after reviewing large pivotal studies with the product.
Using those antibiotics at any dose or frequency greater than what’s recommended would be considered extralabel and, as such, would not be allowed under the current regulation. Overmedicating also would lead to higher costs and potentially violative residues. For those reasons, exceeding the dose or treatment frequency indicated on the label rarely occurs.
Q: Let’s look at the other scenario. On the farm, an unexpected labor shortage or extremes in the weather could potentially stand in the way of treating all pigs for 3 consecutive days. What are the veterinarian’s options in those situations?
JH: Again, every eﬀort should be made to follow the dose and dosing duration provided on the label. However, when those unforeseen, real-world circumstances do arise, it comes down to the attending veterinarian’s judgment to modify treatment from the product label.
For example, how did the pigs respond to the initial treatments? Are they doing better from a health and welfare standpoint? In the end, FDA defers to the veterinarian’s expertise, records and clinical observations to ensure that every eﬀort was made to provide good care and use the products in a safe, judicious and eﬃcacious manner.
Q: Are there other treatment options to ensure administration compliance?
JH: Yes. Veterinarians and producers also could consider using sustained-release antimicrobials such as Draxxin® 25 (tulathromycin) or Excede® (ceftiofur crystalline free acid), which require only one dose. The tradeoﬀ with those products is the longer withdrawal period — 5 days for Draxxin and 14 days for Excede, versus 4 days for Naxcel and 4 days for Excenel RTU EZ (when injection site volumes are 5 mL).
Q: One of the indications for Naxcel, Excede (ceftiofur crystalline free acid) and Excenel RTU EZ is for control of respiratory disease associated with certain pathogens. FDA’s deﬁnition of control is a “drug administered to a group of animals when a proportion of the animals in the group exhibit clinical signs of disease.” Is there a minimum number of animals that have to have clinical signs before the group can be treated with a cephalosporin?
JH: If you use FDA criteria for experimental ﬁeld trails as a guide — speciﬁcally, Guidance for Industry 1782— at least 15% of the group should be exhibiting signs of disease before treatment. This is a starting point, however. In our discussions with regulators about study protocols, FDA’s Center for Veterinary Medicine was open to discussion about reducing that threshold to 10% incidence level to reduce mortality.3 In the ﬁeld, if a group of animals has a history of a disease that has been documented in medical records and a few start breaking with signs of the same disease, treatment may be justiﬁed. Once again, it comes down to the attending veterinarian’s judgement.
Q: How important is laboratory evidence of infection for justifying extralabel use of a cephalosporin?
JH: Veterinarians are allowed to practice veterinary medicine. If they see pigs coughing and breathing hard, they can recommend a cephalosporin if they believe the problem is due to one of the pathogens on the label. Laboratory testing is not required.
However, if the disease gets more severe and pigs are dying, it would be prudent to conduct post-mortems and send samples for testing. Again, this isn’t required, but it’s good practice.
Q: If young pigs on a farm don’t have signs of respiratory disease but they have joint issues and associated lameness — a condition that can be caused by S. suis — can they be treated with a cephalosporin if it’s known their sows are positive for this pathogen? Or would that be considered extralabel, preventive use?
JH: This is a good example of an infectious disease that is not on the label but where extralabel use would be permitted. The cephalosporin must still be prescribed by the veterinarian according to the label at the approved dose, route of administration, frequency and duration of administration.
Q: Is it OK to reconstitute Naxcel to a desired potency for lesser injection volume?
JH: Reconstitution with diﬀerent volumes of sterile water is acceptable as long as the total milligrams an animal receives is according to the label — 3 to 5 mg/kg.
Q: What documentation is acceptable to FDA regarding the use of a cephalosporin?
JH: When a group of pigs is treated with a cephalosporin, don’t rely on anyone’s memory. Write it down, date it and sign it. A document that’s handwritten, dated and signed is golden. The records should include the estimated number of pigs in the facility, the disease and the dosage received, which of course must comply with the label. There should also be an estimate of the total number of pigs treated. I say “estimate” because it’s often not possible to get a completely accurate head count with a large group of pigs. The FDA puts a high value on handwritten, hard copies of medical records.
Q: If there’s a residue violation with a cephalosporin, will handwritten records adequately document compliance for the prescribing veterinarian?
JH: Yes, assuming the cephalosporin was prescribed appropriately. Veterinarians also have the responsibility of ensuring that producers observe required withdrawal periods. I’m aware of several residue-violation cases where veterinarians who prescribed a cephalosporin had accurate treatment records demonstrating compliance with the label and that accounted for the necessary withdrawal time. FDA found the veterinarians did nothing wrong.
Q: What records should be kept when the veterinarian can’t get to the farm and provides a prescription over the phone?
JH: First, there should be a veterinarian-client-patient relationship, as deﬁned by FDA. The swine facility should keep a record of exactly what was prescribed for which animals and when. But veterinarians should make note in their own dated records about who contacted them and what was prescribed. FDA understands that veterinarians can’t always get to a farm, but it may check to see if records from the facility and the veterinarian match.
Q: Are there any common mistakes you see regarding the use of cephalosporins in swine?
JH: It doesn’t happen often, and I know of this happening with diﬀerent types of drugs, not just cephalosporins, but there are cases where farm workers weren’t clear on the instructions or simply grabbed the wrong bottle. To me, this underscores the need for producers to carefully select the employees they permit to administer any medications, not just cephalosporins, and to provide careful training.
IMPORTANT SAFETY INFORMATION
People with known hypersensitivity to penicillin or cephalosporins should avoid exposure to NAXCEL. NAXCEL has a pre-slaughter withdrawal time of four days. Do not use in animals found to be hypersensitive to the product. Click here to see full Prescribing Information.
People with known hypersensitivity to penicillin or cephalosporins should avoid exposure to EXCENEL RTU EZ. Do not use in swine found to be hypersensitive. Withdraw 6 days prior to slaughter when injection site volumes are greater than 5 mL up to 15 mL per injection site and 4 days prior to slaughter when injection site volumes are less than or equal to 5 mL per injection site. Click here to see full Prescribing Information.
Withdraw DRAXXIN/DRAXXIN 25 five (5) days prior to slaughter. Do not use in animals known to be hypersensitive to the product. Click here to see full Prescribing Information.
People with known hypersensitivity to penicillin or cephalosporins should avoid exposure to EXCEDE. Do not use in swine found to be hypersensitive to the product. Pre-slaughter withdrawal time is 14 days following the last dose. Click here to see full Prescribing Information.
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1 Cephalosporin Order of Prohibition Questions and Answers [Internet] FDA [cited August 25, 2019] Available from: https://www.fda.gov/animal-veterinary/antimicrobial-resistance/cephalosporin-order-prohibition-questions- and-answers.
2 Guidance for Industry 178, Recommended Study Design and Evaluation of Effectiveness Studies for Swine Respiratory Disease Claims. U.S. Department of Health and Human Services Food and Drug Administration Center for Veterinary Medicine October 1, 2007.
3 Personal communication.
Posted on November 19, 2019