Monitoring Antifungal Therapy in Horses: Efficacy and Safety

By Dr. Zubair Khalid, DVM, MS, PhD · 2026-08-11

Key Takeaways

• Monitoring antifungal therapy in horses necessitates a dual approach to assess both efficacy and safety, given the inherent toxicity and drug interaction risks of agents like azoles and amphotericin B. Key parameters include clinical lesion scoring, repeat fungal cultures, cytology/histopathology, and targeted organ function tests (hepatic enzymes, renal parameters, hematology).
• Therapeutic efficacy is primarily gauged by clinical lesion resolution (size, depth, exudate, pruritus, pain) and confirmed by mycological cure via repeat fungal culture, though interpretation requires attention to sampling timing and potential for resistance. Ophthalmic examinations with fluorescein staining are critical for keratomycosis, assessing corneal clarity and ulcer progression.
• Safety surveillance focuses on target organ toxicity: azoles necessitate monitoring of hepatic enzymes (AST, GGT, ALP, bilirubin) for hepatotoxicity, while amphotericin B requires serial assessment of renal parameters (creatinine, urea, urinalysis) due to nephrotoxicity. Hematology (CBC, platelet count) is monitored for myelosuppression, though less common.
• Pharmacokinetic principles, particularly oral bioavailability variations among azoles (e.g., fluconazole vs. itraconazole) and nonlinear pharmacokinetics of voriconazole, dictate the potential need for serum drug concentration monitoring (trough/peak levels) to ensure adequate exposure, especially for drugs with narrow therapeutic windows.
• Clinical response is influenced by pathogen susceptibility (e.g., Fusarium species often requiring voriconazole or amphotericin B), host immune status (immunocompromised horses require prolonged therapy and careful surveillance), and infection location/extent (superficial dermatophytosis vs. deep mycoses).
• Establishing a structured monitoring schedule, tailored to the specific infection, antifungal class, and patient comorbidities, is crucial. This schedule should include defined frequencies for clinical assessments, laboratory tests, and imaging, with clear action thresholds for adjusting therapy or re-evaluating the diagnosis.

Fungal infections in horses range from superficial dermatophytosis to deep mycoses involving the respiratory tract, cornea, and disseminated disease. Monitoring antifungal therapy requires a structured approach that evaluates both therapeutic efficacy and drug safety, because the antifungal agents used in equine practice carry meaningful risks of toxicity and drug interactions. This article provides a framework for the veterinary student and practitioner to design monitoring protocols, interpret clinical and laboratory findings, and adjust therapy based on objective criteria.

The clinical questions addressed here are practical: How does one determine whether a fungal infection is responding to treatment? What laboratory parameters signal impending drug toxicity? When should therapy be modified or discontinued? The answers depend on understanding the pharmacology of antifungal drugs, the natural history of the fungal pathogens involved, and the host factors that influence treatment outcome. This first section establishes the scientific foundation for monitoring, including the principles of antifungal pharmacokinetics, the determinants of clinical response, and the rationale for safety surveillance.

At a Glance

Principles of Antifungal Pharmacokinetics and Pharmacodynamics

Antifungal drugs used in horses belong to several classes with distinct mechanisms of action. The polyenes, including amphotericin B, bind ergosterol in the fungal cell membrane and increase permeability. The azoles, including fluconazole, itraconazole, and voriconazole, inhibit lanosterol 14-alpha-demethylase, blocking ergosterol synthesis. The echinocandins inhibit beta-glucan synthase in the fungal cell wall. Each class has characteriztic tissue distribution, elimination pathways, and toxicity profiles that determine which parameters require monitoring.

Oral bioavailability varies substantially among azoles in horses. Fluconazole is well absorbed after oral administration, whereas itraconazole absorption is erratic and highly dependent on the formulation and gastric pH. Voriconazole has good oral bioavailability but exhibits nonlinear pharmacokinetics, meaning that small dose changes can produce disproportionate changes in plasma concentrations. These differences matter clinically because the relationship between dose and exposure is not predictable across drugs, and monitoring serum concentrations may be necessary for agents with narrow therapeutic indices or variable absorption.

The pharmacodynamic index that best predicts antifungal efficacy differs by drug class. For azoles, the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) is the primary predictor of success. For polyenes, the peak concentration to MIC ratio is more relevant. These pharmacodynamic principles, derived largely from human studies and experimental models, inform the design of monitoring protocols in horses, although species-specific validation is limited.

Determinants of Clinical Response

The response to antifungal therapy depends on the interaction between drug, pathogen, and host. Fungal pathogens differ markedly in their intrinsic susceptibility to antifungal agents. Fusarium species, for example, are often resistant to many azoles and require aggressive therapy with agents such as voriconazole or amphotericin B, as described in the review of Fusarium taxonomy and clinical aspects by Nelson and colleagues. In contrast, many dermatophytes are highly susceptible to azoles, and clinical response may be evident within days of initiating treatment.

Host immune status is a critical determinant of outcome. Immunocompromised horses, whether from concurrent disease, stress, or iatrogenic immunosuppression, respond more slowly and are at higher risk of relapse. The principles of managing infection in immunocompromised patients, including the need for prolonged therapy and careful surveillance for secondary infections, are well established in human medicine and apply analogously to equine patients receiving immunosuppressive drugs. The review of graft-versus-host disease by Ferrara and colleagues highlights how immunosuppressed patients require continued monitoring for serious infections during treatment, a principle that transfers directly to equine practice when antifungal therapy is used in compromised horses.

The location and extent of infection also influence the expected time course of response. Superficial dermatophytosis typically responds within two to four weeks, whereas deep mycoses such as pulmonary aspergillosis or systemic mycosis may require months of therapy. Keratomycosis requires frequent ophthalmic re-evaluation because corneal perforation can occur rapidly despite appropriate medical therapy. The review of ophthalmic mycoses by Thomas emphasizes that medical therapy alone does not usually suffice for invasive fungal keratitis, and surgical intervention may be required when lesions do not respond.

Safety Surveillance: Target Organ Toxicity

Hepatotoxicity is the most common serious adverse effect of azole antifungals in horses. The mechanism involves accumulation of toxic intermediates in hepatocytes, leading to hepatocellular injury or cholestasis. Monitoring should include baseline serum biochemistry before therapy and repeat assessment at intervals determined by the drug, dose, and duration of treatment. The MSD Veterinary Manual provides species-specific guidance on interpreting liver enzyme elevations and adjusting therapy accordingly.

Nephrotoxicity is the principal dose-limiting toxicity of amphotericin B. The drug causes renal vasoconstriction and direct tubular injury, and the resulting azotemia may be irreversible with cumulative dosing. Serial measurement of serum creatinine and urea, along with urinalysis to detect casts and proteinuria, is mandatory during amphotericin B therapy. Hydration status should be assessed before each dose, and therapy should be withheld or modified if renal function deteriorates.

Hematologic toxicity is uncommon with most antifungal agents but has been reported with prolonged azole therapy. A complete blood count at baseline and periodically during long-term treatment is reasonable, particularly in horses receiving concurrent medications that may cause myelosuppression.

The Role of Diagnostic Testing in Monitoring

Repeat fungal culture is the definitive method to confirm mycological cure, but interpretation requires attention to sampling technique and timing. Cultures obtained during therapy may be negative because of residual drug in the sample, leading to false reassurance. Conversely, positive cultures late in therapy may indicate either inadequate drug exposure or the emergence of resistance. Susceptibility testing can guide drug selection when clinical response is poor, although breakpoints for equine fungal isolates are not well established.

Cytology and histopathology provide complementary information. Cytologic evaluation of impression smears or aspirates can demonstrate persistent fungal elements and characterize the inflammatory response. Histopathology from biopsy specimens allows assessment of tissue invasion and the depth of infection, which is particularly useful in sinonasal and pulmonary mycoses. The Davis-Thompson Foundation maintains educational pathology resources that illustrate the spectrum of fungal lesions and the tissue responses that indicate resolution or progression.

Monitoring in Specific Clinical Contexts

Keratomycosis

Fungal keratitis requires frequent ophthalmic examination, typically every one to three days in the acute phase. Parameters to assess include the size and depth of the corneal ulcer, the degree of corneal edema, the presence of cellular infiltrate, and the progression of corneal vascularisation. Fluorescein staining documents epithelial healing, and serial photographs provide an objective record of change. Worsening of any parameter despite appropriate therapy warrants reconsideration of the drug choice, the dosing interval, or the need for surgical intervention.

Dermatophytosis

Monitoring dermatophytosis relies primarily on clinical assessment of lesion size, scaling, and hair regrowth. Repeat fungal culture is recommended at the end of the recommended treatment period to confirm elimination of the organizm, because clinical resolution can precede mycological cure. Wood's lamp examination is useful only for Microsporum canis infections and cannot be used to monitor other dermatophytes.

Systemic Mycoses

Deep fungal infections require integration of clinical, imaging, and laboratory monitoring. Serial thoracic radiography or ultrasonography can document resolution of pulmonary lesions. Serum or plasma fungal antigen assays, where available, provide an objective measure of fungal burden, although their sensitivity and specificity in horses are variable. The WOAH terrestrial animal health standards address surveillance principles for reportable fungal diseases and may inform monitoring protocols in regions where specific mycoses are notifiable.

Establishing the Monitoring Schedule

A structured monitoring schedule should be defined at the initiation of antifungal therapy, with parameters selected according to the infection site, the antifungal class, and the horse's signalment and comorbidities. The schedule must be recorded in the medical record and adjusted when the clinical picture changes. For ambulatory patients, the schedule may need to be adapted to owner compliance and travel constraints, but the monitoring intervals should not be extended without a documented rationale.

Re-Evaluation of the Diagnosis

Antifungal therapy is often initiated on the basis of cytology, histopathology, or a strong clinical suspicion before culture results are available. The monitoring period is the time to confirm or revise that initial diagnosis. Culture results should be reviewed when they become available, and susceptibility testing should be interpreted in the context of the clinical response. A lack of response to a drug that the isolate appears susceptible to in vitro should prompt a search for a sequestrum, a foreign body, or an undrained abscess instead of an immediate change in drug class.

The differential diagnosis should be revisited when a lesion fails to improve. Neoplasia, bacterial granuloma, and immune-mediated disease can mimic fungal infection, and the Davis-Thompson Foundation veterinary pathology resources provide case material that illustrates the range of differential diagnoses for chronic nodular and ulcerative skin lesions. Repeat biopsy or culture may be necessary when the initial samples were small or taken from a site with heavy bacterial contamination.

Monitoring the Clinical Response

The clinical response is the most direct measure of therapeutic efficacy. For dermatophytosis, the parameters are lesion diameter, degree of alopecia, scaling, crusting, and the presence of new lesions. Hair regrowth lags behind fungal clearance, so the absence of new lesions and the resolution of crusting are more reliable indicators of response than the return of a normal hair coat. Wood's lamp examination is useful only for strains of Microsporum canis that fluoresce, and a negative examination does not exclude active infection.

For keratomycosis, the monitoring examination should include slit-lamp assessment of corneal thickness, depth of the stromal infiltrate, the character of the corneal surface, and the presence of endothelial plaques or hypopyon. Fluorescein retention defines the margins of the epithelial defect. Worsening corneal edema or an expanding infiltrate despite topical therapy indicates either an incorrect diagnosis, a resistant organizm, or poor drug penetration. The current perspectives on ophthalmic mycoses describe the clinical features that distinguish fungal keratitis from bacterial keratitis and the reasons why medical therapy alone may fail in deep stromal infections.

For systemic mycoses, the monitoring parameters depend on the organ system involved. Serial thoracic radiographs or ultrasonography document the progression or regression of pulmonary lesions. Serial measurement of serum antibody titres or antigen concentrations, where validated for the specific organizm, can support the clinical assessment but should not be used as the sole criterion for discontinuing therapy. The clinical response, including resolution of fever, improved appetite, weight gain, and return to normal exercise tolerance, remains the primary endpoint.

Toxicity Surveillance in the Individual Patient

The toxicity profile of the antifungal agent determines which laboratory parameters require monitoring. The azoles are associated with hepatotoxicity, and serial measurement of hepatic enzyme activity is indicated. The polyenes, particularly amphotericin B, are nephrotoxic, and renal function should be assessed before and during therapy. The echinocandins are less commonly used in horses, but their safety profile in this species is not as well documented as in other species.

The monitoring schedule should be individualised. A horse with pre-existing renal disease receiving an azole may not require the same frequency of renal function testing as a horse receiving amphotericin B, but it does require closer attention to hydration status and concurrent nephrotoxic drugs. A pregnant mare, a neonate, or a geriatric horse may have different metabolic reserves and drug clearance profiles, and the monitoring intervals should reflect those differences.

The MSD Veterinary Manual provides species-specific guidance on the adverse effects of antifungal drugs and the recommended monitoring parameters for each drug class. The clinician should consult the current formulary for the specific drug, formulation, and route of administration before initiating therapy, because the monitoring requirements differ between the topical, oral, and parenteral routes.

Documenting the Monitoring Findings

The medical record should contain a baseline description of the lesion or disease process, including photographs where possible, and a clear statement of the therapeutic endpoint. Each monitoring examination should document the parameters listed in the schedule, the clinician's interpretation of those parameters, and any change in therapy made as a result. Serial photographs are particularly valuable for dermatophytosis and keratomycosis, where subtle changes in lesion size and character may be difficult to describe in words alone.

The record should also document owner communication. The owner should understand the expected duration of therapy, the signs that warrant an immediate call to the clinic, and the consequences of missing a dose or an appointment. For horses in training or competition, the record should note any withdrawal periods that apply to the drugs used, and the owner should be advised to check the rules of the relevant regulatory body. The American Veterinary Medical Association practice resources and the WOAH terrestrial animal health standards provide guidance on professional obligations related to drug use and record keeping, although the specific requirements vary by jurisdiction.

Adjusting Therapy Based on Monitoring Findings

The monitoring findings should feed directly into therapeutic decisions. A lesion that is improving but not resolved at the expected time point may require an extension of therapy at the same dose. A lesion that is static after 14 days of appropriate therapy warrants a repeat culture and susceptibility test, a review of the drug's bioavailability and dosing interval, and consideration of a different drug class. A lesion that is worsening requires immediate re-evaluation of the diagnosis, the drug, and the dose.

The decision to discontinue therapy should be based on clinical resolution, not on the calendar alone. For dermatophytosis, two negative fungal cultures taken one week apart provide stronger evidence of cure than clinical appearance alone. For keratomycosis, the cornea should be re-epithelialised and the stromal infiltrate resolved before topical therapy is stopped, and the frequency of topical application should be tapered instead of stopped abruptly. For systemic mycoses, the clinical signs should have resolved and the imaging findings stabilized before therapy is discontinued, and the horse should be re-examined at intervals after cessation to detect relapse.

Recognized Complications and Early Detection

The principal failure modes in equine antifungal therapy fall into three categories: inadequate drug exposure, unrecognised progression of fungal disease, and drug toxicity that mimics the underlying condition. Each has a characteriztic temporal signature that the monitoring schedule should exploit.

Inadequate drug exposure is the most common early failure. It presents as a plateau in clinical improvement after an initial response, or as failure to improve within the expected window for the lesion type. The discriminating check is a trough or peak concentration measurement where therapeutic drug monitoring is available, combined with verification of owner compliance and correct administration technique. For topical therapy, the more common problem is under-treatment of the lesion margin, particularly in dermatophytosis where hair shafts at the periphery harbour viable spores.

Unrecognised progression is more dangerous. In keratomycosis, deepening corneal opacity, progression to endothelial involvement, or the appearance of hypopyon signals extension beyond the epithelium. In systemic mycoses, new pulmonary nodules, worsening nasal discharge, or the onset of neurological signs indicate hematogenous dissemination. Serial imaging and repeat cytology or culture are the discriminating checks, and their timing should be dictated by the clinical trajectory instead of a fixed calendar.

Drug toxicity that mimics the underlying disease deserves particular attention. Hepatotoxicity from azoles can produce anorexia and lethargy that are easily attributed to the fungal infection itself. The discriminating check is the biochemical profile: rising liver enzyme activity or bilirubin concentration in a horse whose other parameters are stable should trigger dose reduction or a switch in class. Similarly, bone marrow suppression from systemically absorbed drug can present as fever or secondary bacterial infection, and a complete blood count is the appropriate discriminator.

Common Errors and Corrective Actions

Less experienced clinicians most often err in the frequency and interpretation of diagnostic sampling. Repeating fungal culture too early, before drug levels have had time to suppress viable organizms, produces false-negative results that may prompt an unnecessary change in therapy. Conversely, relying on clinical appearance alone in dermatophytosis can lead to premature discontinuation, since hair regrowth lags behind fungal clearance by several weeks.

A second error is the failure to distinguish colonisation from infection in systemic mycoses. A positive culture from a nasal swab or tracheal wash does not confirm invasive disease, and a negative culture does not exclude it when cytology or histopathology shows fungal elements within tissue. The corrective action is to base treatment decisions on tissue invasion demonstrated by cytology, biopsy, or imaging, not on culture results alone. The Davis-Thompson Foundation veterinary pathology resources provide case material that illustrates the distinction between colonisation and tissue invasion.

A third error is the abandonment of a drug class after a single perceived failure without verifying drug exposure. Many apparent azole failures are actually absorption failures, and the same drug at an adjusted dose or with a different formulation may succeed. The corrective action is to document drug levels or to trial a different route before declaring the class ineffective.

Limitations of the Evidence and Divergent Expert Opinion

The evidence base for antifungal monitoring in horses is largely extrapolated from human medicine and from small case series. Controlled comparative trials are scarce, and the pharmacokinetic data that exist are often derived from single-dose studies in small numbers of horses. The MSD Veterinary Manual provides practical monitoring guidance, but it reflects consensus opinion instead of high-grade evidence.

Expert opinion diverges most sharply on two questions. The first is the target trough concentration for azole therapy in horses, some authorities advocate routine therapeutic drug monitoring, while others consider it unnecessary outside refractory cases. The second is the role of combination therapy, the network pharmacology literature suggests that multi-target approaches may reduce resistance emergence, but this has not been translated into equine-specific protocols. Where evidence is contested, the monitoring plan should be individualised and documented, with explicit criteria for escalation.

Referral, Consultation, and Reporting

Referral is warranted when the monitoring schedule reveals progression despite adequate drug exposure, when ocular involvement threatens vision, when systemic disease spreads to new organ systems, or when the diagnosis itself is uncertain. Specialist ophthalmologic referral is appropriate for any keratomycosis that does not improve within the expected window, since surgical intervention may be required. The ophthalmic mycoses literature notes that medical therapy alone does not usually suffice for invasive fungal keratitis due to certain organizms.

Laboratory consultation is indicated when susceptibility testing is required, when unusual organizms such as Fusarium species are isolated, or when histopathology is needed to confirm tissue invasion. The Fusarium species review emphasizes that outcome in fusarial infection is determined by the degree of immunosuppression and the presence of a removable focus, both of which should be assessed in the equine patient.

Regulatory reporting obligations vary by jurisdiction. Where a fungal disease is notifiable, or where drug use falls outside label indications, the attending veterinarian should consult the relevant authority. The WOAH terrestrial animal health standards define international reporting expectations for certain mycoses, and the AVMA practice resources summarize professional obligations in the United States. When in doubt, reporting to the appropriate authority is the safer course.

Frequently Asked Questions

How Should I Monitor Antifungal Therapy When Reference Laboratory Testing Is Unavailable or Cost-Prohibitive?

When culture, susceptibility testing, or serial serum chemistry panels are not feasible, monitoring shifts to rigorous clinical and physical assessment. Serial photography of skin lesions, corneal examination with fluorescein staining, and daily respiratory rate and effort assessment provide objective longitudinal data. For dermatophytosis, Wood's lamp examination remains useful only for select isolates, so response to therapy is judged by hair regrowth and reduction in scaling. The MSD Veterinary Manual provides species-specific guidance on clinical examination findings and lesion characterization that supports this approach. Document findings at each visit with standardized scoring, and maintain a lower threshold for referral when laboratory confirmation is unavailable, because clinical response alone may lag behind mycological cure.

What Minimum Monitoring Is Acceptable for a Horse on Long-Term Oral Azole Therapy in a Field Setting?

A practical minimum includes a baseline complete blood count and serum biochemistry panel before treatment, then repeat biochemistry at two to four weeks and every four to eight weeks thereafter. Liver enzyme activity, particularly gamma-glutamyl transferase and alkaline phosphatase, and bilirubin concentration are the most accessible indicators of hepatotoxicity. Owners should be trained to observe for icterus, reduced appetite, and lethargy between visits. If sampling is logistically difficult, ask the owner to collect blood at the time of routine farrier or vaccination visits. When biochemical monitoring is impossible, reduce the dose only after consulting a current formulary, and document the rationale for the deviation in the medical record.

How Do I Distinguish Disease Progression from Drug Toxicity When Clinical Signs Worsen?

Worsening signs during antifungal therapy require a structured re-evaluation instead of an automatic dose adjustment. First, confirm the original diagnosis by repeat sampling, because a resistant organizm or a second pathogen may have emerged. Second, assess drug bioavailability, including whether the horse is actually receiving the medication and whether gastrointestinal disease could impair absorption. Third, evaluate for drug toxicity using targeted biochemistry and physical examination. For example, progressive keratomycosis with new corneal infiltrate suggests treatment failure, whereas anorexia and icterus suggest hepatotoxicity. The distinction matters because the former may require a different antifungal agent or surgical intervention, while the latter requires dose reduction or drug withdrawal.

What Records Should I Keep Specifically for Antifungal Monitoring Cases?

Maintain a monitoring log that includes the drug, dose, route, and start date, plus a dated clinical score for the target lesion. Record every laboratory result with the reference interval and the laboratory that generated it, because analyzer variation affects interpretation. Document owner-reported observations such as appetite, demeanour, and medication administration compliance. Note any concurrent medications, because drug interactions can alter antifungal metabolism and toxicity risk. Photographs should be standardized by position, lighting, and distance. The AVMA practice resources offer guidance on medical record content and retention that applies to these cases. These records support both clinical decisions and defensible communication if a referral or dispute arises.

How Do I Explain the Need for Ongoing Monitoring to an Owner Who Wants to Stop Treatment Early?

Frame monitoring as the tool that determines when treatment can safely stop, not as an obstacle to finishing. Explain that clinical improvement often precedes mycological cure, and that stopping early risks relapse with a more resistant organizm. Use concrete terms: the lesion may look healed while fungal elements persist in tissue. Show the owner the monitoring schedule and what each test is designed to detect, such as liver enzyme changes that are usually reversible if caught early. Offer a practical compromise, such as extending the interval between blood tests, but do not compromise on the end-point criteria for stopping therapy. Written instructions with a calendar help owners see the finite duration of the commitment.

Does Monitoring Differ for a Foal or a Pregnant Mare Compared with an Adult Horse?

Yes, age and reproductive status alter both drug handling and the consequences of toxicity. Hepatic drug metabolism is immature in neonates and changes rapidly in the first months of life, so more frequent biochemistry is warranted. Pregnant mares require consideration of fetal drug exposure, and the evidence base for antifungal safety in equine pregnancy is limited. The WOAH terrestrial animal health standards emphasize that treatment decisions in breeding animals should account for broader population and trade implications. In both groups, choose the least toxic effective agent and document the risk-benefit reasoning. Monitor body weight frequently in foals because dose adjustments are needed as they grow, and consult a current formulary for any dose change.

Related Clinical & Scientific Guides

• Hypersensitivity Reactions: Types and Mechanisms
• Therapeutic Decision-Making for Respiratory Infections in Cattle
• Monitoring Fluid Therapy in Critically Ill Veterinary Patients

References and Further Reading

• Graft-versus-host disease.. 2009.
• Stenotrophomonas maltophilia: an emerging global opportunistic pathogen.. 2012.
• Structure and dynamics of molecular networks: a novel paradigm of drug discovery: a comprehensive review.. 2013.
• Taxonomy, biology, and clinical aspects of Fusarium species.. 1994.
• Current perspectives on ophthalmic mycoses.. 2003.
• Davis-Thompson Foundation Veterinary Pathology Resources. Davis-Thompson Foundation.
• MSD Veterinary Manual, Professional Edition. MSD Veterinary Manual.
• American Veterinary Medical Association Practice Resources. American Veterinary Medical Association.
• WOAH Terrestrial Animal Health Code. WOAH.

Related Articles

• Monitoring Analgesic Therapy in Horses: A Practical Guide
• Monitoring Corticosteroid Therapy in Veterinary Dermatology
• Decision Framework for Choosing Antifungal Therapy in Veterinary Patients
• Monitoring Immunosuppressive Therapy in Veterinary Patients
• Monitoring Endocrine Therapy in Veterinary Patients: Insulin and Beyond

This article is educational professional reference material for veterinary audiences. It is not a substitute for veterinary diagnosis, individual clinical judgment, current product labeling, or applicable regulatory requirements.