Animal drug shortages limit veterinary therapeutic options and introduce artifacts in antimicrobial sales reporting.

Supply chain issues disrupt veterinary care and cause downstream consequences that alter the practice of veterinary medicine. Antimicrobials are just 1 class of pharmaceuticals that have been impacted by supply chain issues over the last couple of years. Since February 2021, 2 sponsors/manufacturers of penicillin products have reported shortages in the active pharmaceutical ingredient. With the release of the 2021 Summary Report on Antimicrobials Sold or Distributed for Use in Food-Producing Animals by the FDA, a key finding was a 19% decrease in penicillin sales and distribution from 2020 to 2021. Herein, we provide our clinicians' professional perspective regarding how drug shortages, specifically that of penicillin, might contribute to misconstrued patterns in antimicrobial use and what can be done by veterinarians and the FDA to minimize the impact of an antimicrobial drug shortage on animal health and well-being.

Antimicrobial resistance in multistate outbreaks of nontyphoidal Salmonella infections linked to animal contact-United States, 2015-2018.

Animal contact is an established risk factor for nontyphoidal Salmonella infections and outbreaks. During 2015-2018, the U.S. Centers for Disease Control and Prevention (CDC) and other U.S. public health laboratories began implementing whole-genome sequencing (WGS) of Salmonella isolates. WGS was used to supplement the traditional methods of pulsed-field gel electrophoresis for isolate subtyping, outbreak detection, and antimicrobial susceptibility testing (AST) for the detection of resistance. We characterized the epidemiology and antimicrobial resistance (AMR) of multistate salmonellosis outbreaks linked to animal contact during this time period. An isolate was considered resistant if AST yielded a resistant (or intermediate, for ciprofloxacin) interpretation to any antimicrobial tested by the CDC or if WGS showed a resistance determinant in its genome for one of these agents. We identified 31 outbreaks linked to contact with poultry (n = 23), reptiles (n = 6), dairy calves (n = 1), and guinea pigs (n = 1). Of the 26 outbreaks with resistance data available, we identified antimicrobial resistance in at least one isolate from 20 outbreaks (77%). Of 1,309 isolates with resistance information, 247 (19%) were resistant to ≥1 antimicrobial, and 134 (10%) were multidrug-resistant to antimicrobials from ≥3 antimicrobial classes. The use of resistance data predicted from WGS increased the number of isolates with resistance information available fivefold compared with AST, and 28 of 43 total resistance patterns were identified exclusively by WGS; concordance was high (>99%) for resistance determined by AST and WGS. The use of predicted resistance from WGS enhanced the characterization of the resistance profiles of outbreaks linked to animal contact by providing resistance information for more isolates.

Decision making on antimicrobial use: Cat and dog owners' knowledge and preferences for veterinary communication.

BACKGROUND: Veterinarians' understanding of cat and dog owners' perceptions about antimicrobial use will enhance their ability to communicate with clients to uphold antimicrobial stewardship guidelines. METHODS: A total of 571 cat and dog owners were surveyed via an online platform to understand their antimicrobial knowledge and preferences for veterinary communication in antimicrobial use decision making. Data were analysed descriptively and inferentially to determine relationships between variables. RESULTS: Cat and dog owners' backgrounds had an impact their antimicrobial knowledge. Women, individuals with a university degree, those with a health/science background and those identifying as white had a higher level of knowledge of antibiotics and antibiotic resistance. Owners' trust in veterinarians positively impacts adherence to recommendations. Where there was a strong preference for one type of messaging regarding antimicrobial use and stewardship, the owner's background was not predictive of a difference in response. LIMITATIONS: The study population was mostly white, which reflects the US population and the reported distribution of pet owners who own dogs and cats. Respondents may have been susceptible to recall bias and/or social desirability bias. CONCLUSION: Veterinarians should tailor their communication to meet clients' level of knowledge and rely on competent communication to enhance understanding and facilitate adherence to antimicrobial stewardship guidelines.

Prevalence of antibiotic use for dogs and cats in United States veterinary teaching hospitals, August 2020.

BACKGROUND: Awareness of prescribing practices helps identify opportunities to improve antibiotic use (AU). OBJECTIVES: To estimate AU prevalence in dogs and cats in U.S. veterinary teaching hospitals (VTHs) and identify antibiotic drugs commonly prescribed, indications for use, and evidence of bacterial infection. ANIMALS: Medical record data were collected from dogs and cats examined at 14 VTHs. METHODS: Data were collected from VTH medical records of dogs and cats examined by primary care, urgent care, emergency and critical care, internal medicine, and surgery services on a single day during August 13-September 3, 2020. Data included signalment; clinical service; inpatient or outpatient status; clinical conditions; diagnostic tests; evidence of bacterial infection; intended reason for AU; name and route of antibiotics prescribed. RESULTS: Of 883 dogs and cats, 322 (36.5%) were prescribed at least 1 antibiotic. Among 285 antibiotics administered systemically intended for treatment of infection, 10.9% were prescribed without evidence of infection. The most common class of antibiotics presribed for systemic administration was potentiated penicillin for dogs (115/346, 33.3%) and cats (27/80, 33.8%). For dogs and cats, first-generation cephalosporins (93/346, 26.9% and 11/80, 13.8%, respectively) and fluoroquinolones (51/346, 14.7% and 19/80, 23.8%, respectively) was second or third most-prescribed. Common AU indications included skin, respiratory, and urinary conditions, and perioperative use. CONCLUSIONS AND CLINICAL IMPORTANCE: Collaborative data collection provides a sustainable methodology to generate national AU prevalence estimates and bring attention to areas requiring additional research and detailed data collection. These efforts can also identify practice improvement opportunities in settings where future veterinarians are trained.

Antibiograms as one-health tools for antimicrobial stewardship: California's experience with livestock antibiogram development.

Antibiograms are collections of antimicrobial susceptibility data for a particular bacterial organism and host species. Antibiograms are important tools for antimicrobial stewardship, as they may be used to guide empiric antimicrobial therapy and assess trends in antimicrobial resistance, maximizing treatment success and preserving the efficacy of currently available pharmaceuticals. Targeted use of antimicrobials is critically important to minimize the spread of antimicrobial resistance, which may be conveyed between animals and humans directly but may also be spread through the environment and ecological niches, such as soil, water, and wildlife reservoirs. To effectively utilize antibiograms as part of a comprehensive antimicrobial stewardship plan, veterinarians need to know data characteristics, including the source population, body site (when possible), and number of isolates included, in addition to the animal species and bacterial organisms for which each breakpoint was developed. Although widely used in human health systems, antibiograms are not often available in veterinary medicine. This paper describes antibiogram creation and use, discusses antibiogram development by US veterinary diagnostic laboratories, and shares California's process to create and promote livestock antibiograms. The companion Currents in One Health article by Burbick et al, AJVR, September 2023, addresses the benefits and challenges associated with developing veterinary antibiograms.

Benefits and challenges of creating veterinary antibiograms for empiric antimicrobial selection in support of antimicrobial stewardship and advancement of one-health goals.

Antibiograms are important tools for antimicrobial stewardship that are often underutilized in veterinary medicine. Antibiograms summarize cumulative antimicrobial susceptibility testing (AST) data for specific pathogens over a defined time period; in veterinary medicine, they are often stratified by host species and site of infection. They can aid practitioners with empiric therapy choices and assessment of antimicrobial resistance trends within a population in support of one-health goals for antimicrobial stewardship. For optimal application, consideration must be given to the number of isolates used, the timeframe of sample collection, laboratory analytical methodology, and the patient population contributing to the data (eg, treatment history, geographic region, and production type). There are several limitations to veterinary antibiograms, including a lack of breakpoint availability for bacterial species, a lack of standardization of laboratory methodology and technology for culture and AST, and a lack of funding to staff veterinary diagnostic laboratories at a level that supports antibiogram development and education. It is vital that veterinarians who use antibiograms understand how to apply them in practice and receive relevant information pertaining to the data to utilize the most appropriate antibiogram for their patients. This paper explores the benefits and challenges of developing and using veterinary antibiograms and proposes strategies to enhance their applicability and accuracy. Further detail regarding the application of veterinary antibiograms by privately practicing clinicians is addressed in the companion Currents in One Health article by Lorenz et al (JAVMA, September 2023).

Impacts of the COVID-19 pandemic on antimicrobial use in companion animals in an academic veterinary hospital in North Carolina.

Antimicrobial resistance (AMR) in bacterial pathogens reduces the effectiveness of these drugs in both human and veterinary medicine, making judicious antimicrobial use (AMU) an important strategy for its control. The COVID-19 pandemic modified operations in both human and veterinary healthcare delivery, potentially impacting AMU. The goal of this research is to quantify how antimicrobial drug prescribing practices for companion animals in an academic veterinary hospital changed during the pandemic. A retrospective study was performed using prescribing data for dogs and cats collected from the NC State College of Veterinary Medicine (NCSU-CVM) pharmacy, which included prescriptions from both the specialty referral hospital and primary care services. Records (n = 31,769) for 34 antimicrobial drugs from 2019-2020-before and during the pandemic-related measures at the NCSU-CVM-were compared. The prescribed antimicrobials' importance was categorized using the FDA's Guidance for Industry (GFI #152), classifying drugs according to medical importance in humans. A proportional odds model was used to estimate the probability of more important antimicrobials being administered in patients seen during the pandemic versus before (i.e., critically important vs. highly important vs. important). Rates of AMU per week and per patient visit were also compared. During the pandemic, cumulative antimicrobials prescribed per week were significantly decreased in most services for dogs. Weekly rates for Highly Important antimicrobials were also significantly lower in dogs. For important and critically important antimicrobials, rates per week were significantly decreased in various services overall. Rates of antimicrobial administration per patient visit were significantly increased for Highly Important drugs. Patients in the internal medicine, dermatology, and surgery services received significantly more important antimicrobials during the pandemic than before, while cardiology patients received significantly less. These results suggest that the pandemic significantly impacted prescribing practices of antimicrobials for companion animals in this study.

Enhancing Veterinary Student Engagement in Public Health and Epidemiology Coursework through a Client-Focused Risk Communication Assignment.

The ongoing COVID-19 pandemic has highlighted the important role veterinarians play as public health communicators and emphasized the importance of engaging veterinary students in epidemiology and public health curriculum, the majority of whom have a clinical focus and struggle to see their relevance in relation to future career plans. To enhance student engagement, second-year DVM students were asked to create a one-page risk communication handout centered on a zoonotic disease and organized with public health message mapping. Informed by the distribution of students' self-declared career plans at admission to the DVM program, students were asked to choose from a list of zoonotic pathogens previously covered in the DVM curriculum and to select a relevant focus species and expected lay audience member. This assignment was scaffolded with previous infectious disease and communication coursework and provided an opportunity for all students to engage with public health material regardless of prior interest or knowledge. Students chose 13 of 15 zoonotic diseases provided, and their species and audience focuses were distributed across previously stated career focuses, including companion animals, food producing animals, exotic animals, and wildlife. Providing options relevant to diverse student experiences and connecting the assignment to clinical competencies supported student autonomy and engagement in public health content outside clinically focused core classes. Students' successful delivery of constructive peer feedback indicated their engagement with the public health course material, integration of learning from other parts of the curriculum, and perceived relevance of the assignment to their future career focus.

Development of a method for creating antibiograms for use in companion animal private practices.

OBJECTIVE: To identify a method for developing antibiograms for use in companion animal private practices (PPs). SAMPLES: Reports (n = 532) of aerobic bacterial culture and antimicrobial susceptibility testing performed between January 1, 2018, and December 31, 2018, at 11 PPs and 1 academic primary care practice (APCP). PROCEDURES: Data extracted from reports included patient identification number, laboratory accession number, patient signalment, collection method, body site, and results of bacterial culture and antimicrobial susceptibility testing. A custom antibiogram was then constructed with the help of commonly available software by adapting methods used by human hospitals. Susceptibility patterns of bacteria isolated by PPs and the APCP were compared to identify challenges associated with collating data from multiple laboratories. RESULTS: 4 bacterial species (Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, and Staphylococcus pseudintermedius) and 3 bacterial groups (Enterobacteriaceae, Enterococcus spp, and coagulase-positive Staphylococcus spp) met the minimum requirement of ≥ 15 isolates for construction of an antibiogram. For urine samples, 3 bacterial species and 2 bacterial groups met the minimum requirement of ≥ 10 isolates. For samples from skin, 2 bacterial species and 2 bacterial groups met the minimum requirement of ≥ 10 isolates. Patient signalment, sample source, and distribution of bacterial isolates were similar between PP and APCP patients. CONCLUSIONS AND CLINICAL RELEVANCE: Results demonstrated that it was feasible to adapt existing guidelines for developing antibiograms in human medicine to the veterinary outpatient setting. Use of antibiograms could aid in empirical antimicrobial drug selection in a manner that supports antimicrobial stewardship principles.

DLK Activation Synergizes with Mitochondrial Dysfunction to Downregulate Axon Survival Factors and Promote SARM1-Dependent Axon Degeneration.

Axon degeneration is a prominent component of many neurological disorders. Identifying cellular pathways that contribute to axon vulnerability may identify new therapeutic strategies for maintenance of neural circuits. Dual leucine zipper kinase (DLK) is an axonal stress response MAP3K that is chronically activated in several neurodegenerative diseases. Activated DLK transmits an axon injury signal to the neuronal cell body to provoke transcriptional adaptations. However, the consequence of enhanced DLK signaling to axon vulnerability is unknown. We find that stimulating DLK activity predisposes axons to SARM1-dependent degeneration. Activating DLK reduces levels of the axon survival factors NMNAT2 and SCG10, accelerating their loss from severed axons. Moreover, mitochondrial dysfunction independently decreases the levels of NMNAT2 and SCG10 in axons, and in conjunction with DLK activation, leads to a dramatic loss of axonal NMNAT2 and SCG10 and evokes spontaneous axon degeneration. Hence, enhanced DLK activity reduces axon survival factor abundance and renders axons more susceptible to trauma and metabolic insult.

The AVMA's definitions of antimicrobial uses for prevention, control, and treatment of disease.

Recent state and federal legislative actions and current recommendations from the World Health Organization seem to suggest that, when it comes to antimicrobial stewardship, use of antimicrobials for prevention, control, or treatment of disease can be ranked in order of appropriateness, which in turn has led, in some instances, to attempts to limit or specifically oppose the routine use of medically important antimicrobials for prevention of disease. In contrast, the AVMA Committee on Antimicrobials believes that attempts to evaluate the degree of antimicrobial stewardship on the basis of therapeutic intent are misguided and that use of antimicrobials for prevention, control, or treatment of disease may comply with the principles of antimicrobial stewardship. It is important that veterinarians and animal caretakers are clear about the reason they may be administering antimicrobials to animals in their care. Concise definitions of prevention, control, and treatment of individuals and populations are necessary to avoid confusion and to help veterinarians clearly communicate their intentions when prescribing or recommending antimicrobial use.

HSP90 is a chaperone for DLK and is required for axon injury signaling.

Peripheral nerve injury induces a robust proregenerative program that drives axon regeneration. While many regeneration-associated genes are known, the mechanisms by which injury activates them are less well-understood. To identify such mechanisms, we performed a loss-of-function pharmacological screen in cultured adult mouse sensory neurons for proteins required to activate this program. Well-characterized inhibitors were present as injury signaling was induced but were removed before axon outgrowth to identify molecules that block induction of the program. Of 480 compounds, 35 prevented injury-induced neurite regrowth. The top hits were inhibitors to heat shock protein 90 (HSP90), a chaperone with no known role in axon injury. HSP90 inhibition blocks injury-induced activation of the proregenerative transcription factor cJun and several regeneration-associated genes. These phenotypes mimic loss of the proregenerative kinase, dual leucine zipper kinase (DLK), a critical neuronal stress sensor that drives axon degeneration, axon regeneration, and cell death. HSP90 is an atypical chaperone that promotes the stability of signaling molecules. HSP90 and DLK show two hallmarks of HSP90-client relationships: (i) HSP90 binds DLK, and (ii) HSP90 inhibition leads to rapid degradation of existing DLK protein. Moreover, HSP90 is required for DLK stability in vivo, where HSP90 inhibitor reduces DLK protein in the sciatic nerve. This phenomenon is evolutionarily conserved in Drosophila Genetic knockdown of Drosophila HSP90, Hsp83, decreases levels of Drosophila DLK, Wallenda, and blocks Wallenda-dependent synaptic terminal overgrowth and injury signaling. Our findings support the hypothesis that HSP90 chaperones DLK and is required for DLK functions, including proregenerative axon injury signaling.

TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca2+/PKA Signaling.

Preconditioning nerve injuries activate a pro-regenerative program that enhances axon regeneration for most classes of sensory neurons. However, nociceptive sensory neurons and central nervous system neurons regenerate poorly. In hopes of identifying novel mechanisms that promote regeneration, we screened for drugs that mimicked the preconditioning response and identified a nociceptive ligand that activates a preconditioning-like response to promote axon outgrowth. We show that activating the ion channel TRPV1 with capsaicin induces axon outgrowth of cultured dorsal root ganglion (DRG) sensory neurons, and that this effect is blocked in TRPV1 knockout neurons. Regeneration occurs only in NF200-negative nociceptive neurons, consistent with a cell-autonomous mechanism. Moreover, we identify a signaling pathway in which TRPV1 activation leads to calcium influx and protein kinase A (PKA) activation to induce a preconditioning-like response. Finally, capsaicin administration to the mouse sciatic nerve activates a similar preconditioning-like response and induces enhanced axonal outgrowth, indicating that this pathway can be induced in vivo. These findings highlight the use of local ligands to induce regeneration and suggest that it may be possible to target selective neuronal populations for repair, including cell types that often fail to regenerate.

An evolutionarily conserved mechanism for cAMP elicited axonal regeneration involves direct activation of the dual leucine zipper kinase DLK.

A broadly known method to stimulate the growth potential of axons is to elevate intracellular levels of cAMP, however the cellular pathway(s) that mediate this are not known. Here we identify the Dual Leucine-zipper Kinase (DLK, Wnd in Drosophila) as a critical target and effector of cAMP in injured axons. DLK/Wnd is thought to function as an injury 'sensor', as it becomes activated after axonal damage. Our findings in both Drosophila and mammalian neurons indicate that the cAMP effector kinase PKA is a conserved and direct upstream activator of Wnd/DLK. PKA is required for the induction of Wnd signaling in injured axons, and DLK is essential for the regenerative effects of cAMP in mammalian DRG neurons. These findings link two important mediators of responses to axonal injury, DLK/Wnd and cAMP/PKA, into a unified and evolutionarily conserved molecular pathway for stimulating the regenerative potential of injured axons.

Cytoskeletal disruption activates the DLK/JNK pathway, which promotes axonal regeneration and mimics a preconditioning injury.

Nerve injury can lead to axonal regeneration, axonal degeneration, and/or neuronal cell death. Remarkably, the MAP3K dual leucine zipper kinase, DLK, promotes each of these responses, suggesting that DLK is a sensor of axon injury. In Drosophila, mutations in proteins that stabilize the actin and microtubule cytoskeletons activate the DLK pathway, suggesting that DLK may be activated by cytoskeletal disruption. Here we test this model in mammalian sensory neurons. We find that pharmacological agents designed to disrupt either the actin or microtubule cytoskeleton activate the DLK pathway, and that activation is independent of calcium influx or induction of the axon degeneration program. Moreover, activation of the DLK pathway by targeting the cytoskeleton induces a pro-regenerative state, enhancing axon regeneration in response to a subsequent injury in a process akin to preconditioning. This highlights the potential utility of activating the DLK pathway as a method to improve axon regeneration. Moreover, DLK is required for these responses to cytoskeletal perturbations, suggesting that DLK functions as a key neuronal sensor of cytoskeletal damage.