Comparison between Oral Terbinafine and Oral Itraconazole for the Treatment of Onychomycosis within Podiatry

Onychomycosis is a common fungal nail infection which is caused by dermatophytes, yeasts, and saprophytic mould infections (Elewski, 1998). Data suggests that the prevalence of onychomycosis may be at least 20% in individuals aged 60 years or older and over 50% in those aged 70 years or older (Gupta et al., 2022). Treatment of onychomycosis has been attempted within podiatry with little success until recent years, early remedies focused on topical treatments, driven by the belief that the condition was caused by a superficial issue (Del Rosso, 1997). Commonly used topical agents for localised dermatophytic infections include imidazoles (such as ketoconazole, econazole, and oxiconazole), allylamines (including naftifine and terbinafine hydrochloride), topical 5% ciclopirox and topical 5% amorolfine (Tabara et al., 2015). These topical medications are generally ineffective against nail fungal infections because they cannot fully penetrate the nail unit to eliminate the infection. It was only after recognizing the fungal nature of these locally invasive infections that systemically active drugs for onychomycosis were developed (Barranco, 1995). Two of the most common prescribed oral drugs for onychomycosis include terbinafine and itraconazole, the later belonging to the family of azoles (Kreijkamp-Kaspers et al., 2017).

In this critique, we will evaluate three studies that compare these two systemic antifungal drugs and assess their applicability for use in podiatry. After analysing the strengths, limitations, and clinical implications of each study, we will recommend which drug is more suitable for podiatric practice with appropriate patient considerations.

The study by Evans and Sigurgeirsson (1999) offers a real-world comparative analysis of terbinafine and itraconazole for the treatment of toenail onychomycosis. Unlike many commercially sponsored studies, which maybe inclined to exaggerate benefits for one treatment, this independent study potentially provides a less biased evaluation of the two drug’s effectiveness. Terbinafine was administered at 250 mg daily for three months, while itraconazole was given in a pulse regimen (400 mg daily for one week per month over three cycles). The study examined both mycological cure rates (the elimination of the fungal infection as confirmed by lab tests) and subjective outcomes like patient satisfaction.

One of the study's major strengths is its focus on treatment effectiveness, which evaluates how these drugs perform in a real-world setting where factors like patient compliance and variations in treatment protocols may influence outcomes. The inclusion of subjective outcome measures, such as patient satisfaction using a Visual Analogue Scale (VAS), provides insights into the patient experience (Voutilainen et al., 2015), a critical factor in managing a chronic and often visible condition like onychomycosis. Moreover, the independent nature of the study adds credibility, as it avoids the commercial bias typically seen in industry-funded research (Lexchin et al., 2003).

The study also demonstrated that terbinafine had a slight advantage over itraconazole, with a mycological cure rate of 70.6% versus 62.8%, respectively. More significantly, patient satisfaction was much higher with terbinafine, especially among older patients and women, suggesting that terbinafine may offer a more comfortable or preferable treatment experience for these groups.

While the study provides valuable real-world data, it is not without limitations. First, the retrospective design limits the ability to control for confounding factors, such as the severity of the infection, patient health status, or compliance levels, all of which could influence outcomes. The lack of randomisation in assigning patients to terbinafine or itraconazole could also introduce bias, as patients might have been pre-selected for certain treatments based on characteristics not accounted for in the study. Additionally, the sample size of 117 patients (74 on terbinafine and 43 on itraconazole) is relatively small, reducing the study's statistical power to detect significant differences between the two treatments.

From a podiatric perspective, the study suggests that terbinafine may be the better option for older patients and women, populations commonly encountered in podiatry practices. These patients are likely to benefit from the higher satisfaction rates with terbinafine, as demonstrated in the study. Furthermore, the slightly better mycological cure rates, combined with a greater ease of administration (a daily pill rather than pulse dosing), makes terbinafine a more attractive choice for ensuring compliance in long-term treatments common in podiatry. In contrast, itraconazole may still be useful in specific cases, but terbinafine’s overall advantages in patient satisfaction and slightly better outcomes make it a strong contender as the first choice.

A further study by Bräutigam et al. (1995) is a multicentre, double-blind, randomized trial comparing terbinafine and itraconazole in the treatment of toenail onychomycosis, with a follow-up period of 52 weeks. Patients were given either 250 mg of terbinafine daily or 200 mg of itraconazole daily for 12 weeks, with outcomes measured at the end of treatment and throughout the follow-up period. The primary outcome was mycological cure (negative microscopy and culture), with secondary outcomes including the length of unaffected nail growth and adverse events.

This study's strengths lie in its robust design: randomized, double-blind, and including a large sample size (195 patients), however, the absence of a placebo control prevents this from meeting the "gold standard" criteria for an interventional study design (Misra, 2012). The methodology does however minimise biases and enhances the reliability of the findings. Furthermore, the long follow-up period of 52 weeks allows for an extensive assessment of both the initial treatment efficacy and the long-term sustainability of results (Ouyang et al., 2020), which is critical for chronic conditions like onychomycosis that have high relapse rates.

The results strongly favoured terbinafine, which achieved a mycological cure rate of 81% compared to 63% for itraconazole. Negative culture results were also significantly higher in the terbinafine group (92% vs. 67%), and the length of unaffected nail was greater in patients treated with terbinafine. These findings suggest that terbinafine not only clears the infection more effectively but also leads to quicker and more substantial nail recovery, a key factor for patients seeking cosmetic improvement, as evidence suggests onychomycosis negatively impacts quality of life, particularly by diminishing self-esteem and hindering social interactions (Scher, 1994).

While the study design is strong, it does have some limitations. The exclusion of patients with comorbidities such as renal or hepatic disease, as well as those receiving immunosuppressive treatments, limits the generalisability of the results to a broader, more clinically diverse population which is commonly encountered within podiatry (Salmasi et al., 2022). Furthermore, the study did not evaluate subjective outcomes such as patient satisfaction or quality of life, which could be relevant in a condition like onychomycosis that often causes significant cosmetic and psychological distress.

Both drugs were well tolerated by most patients, with only a few reporting side effects. The pattern of adverse events was consistent with the known profiles of these drugs, such as gastrointestinal complaints, headaches, and taste disturbances. Importantly, only a few patients discontinued treatment due to side effects, and no severe adverse events were reported. This demonstrates that both terbinafine and itraconazole are relatively safe for treating onychomycosis, although patients on terbinafine reported a slightly higher incidence of taste disturbances (4 patients vs. 3 for itraconazole), including one case of severe taste loss lasting up to 14 weeks.

`The potential for bias was present as the study was funded by Novartis Pharmaceuticals, which developed terbinafine. Although the study was designed to minimise bias through randomization and blinding, the potential for subtle bias cannot be entirely ruled out in industry-sponsored trials. The conclusions that terbinafine is clearly superior could have been influenced by the funding source, even unintentionally (Lexchin et al., 2003).

While the 52-week follow-up period offers valuable insights into the long-term effectiveness and relapse rates, such an extended period might not be practical for many clinical settings. The length of the study could also result in a higher dropout rate, although this was not specifically reported which is a limitation in study design (Shih, 2002). A shorter, more focused follow-up might have sufficed to draw similar conclusions while being more aligned with clinical practice.

For podiatric practice, the findings from this study provide strong evidence in favour of terbinafine as the first-line treatment for toenail onychomycosis. The higher cure rates and faster clinical improvement with terbinafine make it a more effective choice, particularly in cases where patients seek faster resolution of symptoms or have experienced previous treatment failures. The fact that terbinafine shows greater effectiveness in more severe infections (i.e., those involving more than 60% of the nail) adds to its clinical value, especially in a podiatric setting where patients often present with advanced disease.

However, the slightly higher incidence of taste disturbances with terbinafine may be of concern to some patients, particularly those who are sensitive to sensory changes. Additionally, podiatrists should remain cautious about liver enzyme monitoring, especially in patients with pre-existing liver conditions or prolonged treatment courses.

In conclusion, the Bräutigam (1998) study offers robust evidence that terbinafine is more effective than itraconazole for treating toenail onychomycosis. Its faster time to cure, higher mycological success rates, and good safety profile make it a strong candidate for first-line treatment in podiatry. Nevertheless, careful patient selection and monitoring for adverse effects, particularly regarding liver function and taste disturbances, are essential to ensure optimal treatment outcomes.

The third and final study to be in included is Etgü (2023) which provides a retrospective analysis of liver enzyme abnormalities in patients treated with terbinafine and itraconazole for onychomycosis in 735 patients. The primary objective was to assess the impact of these oral antifungal treatments on liver enzymes, focusing on their safety profiles, particularly in relation to hepatotoxicity. The study observed patients' aspartate transaminase (AST) and alanine aminotransferase (ALT) levels before treatment and after one month to gauge potential liver damage, a known risk factor with systemic antifungal agents.

The study's inclusion of 735 patients enhances the reliability of its findings. A large sample size allows for more generalisable results and offers a more accurate reflection of the real-world population being treated for onychomycosis.

Given the known risks of liver enzyme abnormalities with terbinafine and itraconazole, this study's focus on hepatotoxicity is clinically relevant. The study provides valuable insights into the prevalence of liver enzyme elevation, particularly with terbinafine, which is known to carry a higher risk of hepatotoxicity. This is important for podiatrists, as systemic antifungals are commonly used in onychomycosis treatment, and the potential for liver damage can be a critical consideration in certain patients.

The study compares both terbinafine and itraconazole, providing insights into how each drug affects liver function. By evaluating both drugs, the study helps clinicians understand the relative risks of hepatotoxicity between these two common treatments. The data showed that 8.4% of patients on terbinafine experienced elevated ALT levels, compared to 7.5% on itraconazole. Additionally, 5.2% of patients on terbinafine experienced elevated AST levels, while none of the patients on itraconazole experienced elevated AST levels.

The retrospective nature of the study limits its ability to control for confounding factors such as the presence of other medications that the participants may be taking that may affect liver enzymes or pre-existing liver conditions. While retrospective studies are valuable for analysing real world data, they inherently lack the rigor of randomized controlled trials (RCTs), which can better establish causal relationships, although neither RCT’s nor observational studies can provide answers to every research question in all situations (Fernainy et al., 2024).

The absence of randomisation is a notable limitation (Chiò et al., 2009). Patients were not randomly assigned to receive terbinafine or itraconazole, and the choice of drug may have been influenced by patient specific factors such as age, comorbidities, or physician preference. This could introduce selection bias, as patients at higher risk for hepatotoxicity might have been prescribed itraconazole instead of terbinafine, skewing the safety results.

The follow-up period of just one month is also insufficient for evaluating the long-term hepatotoxic effects of these medications (Fitzpatrick et al., 2018). While the study did provide data for a few patients up to four months, this duration is short considering that antifungal treatments for onychomycosis often last up to three to six months, and liver damage can occur later in treatment. Ideally, longer follow-up periods would provide a more comprehensive understanding of the risks involved.

One of the key takeaways from this study is the need for routine liver enzyme monitoring when prescribing systemic antifungals, particularly terbinafine. Given that 8.4% of patients on terbinafine experienced elevated ALT levels, it is critical for podiatrists to conduct baseline liver function tests and continue monitoring throughout treatment. The study highlights that while the overall risk of severe liver damage is low, proactive monitoring is essential to prevent complications.

The study reinforces the importance of tailoring treatment based on individual patient risk factors (Baker et al., 2010). For patients with pre-existing liver conditions or those on hepatotoxic medications, itraconazole may be a safer option given its lower incidence of elevated AST levels. Podiatrists should carefully assess patients' medical histories and consider alternative treatments, such as topical antifungals, for high-risk patients.

Podiatrists should emphasise the importance of follow-up appointments to monitor liver function. The study shows that a large proportion of patients were lost to follow-up, which may result in missed opportunities to detect early signs of liver toxicity.

The choice between terbinafine and itraconazole should weigh the benefits of terbinafine’s higher cure rate against the risks of hepatotoxicity, with a preference for itraconazole or topical treatments in patients over 65 or those with additional risk factors for liver disease.

The three studies discussed in this analysis provide a robust comparison of these two systemic medications, helping guide their use in podiatric practice. By synthesising the results of these studies, this analysis will evaluate their collective findings and discuss the implications for effective and safe onychomycosis treatment in podiatry.

The comparative analysis of terbinafine and itraconazole across several studies highlights key differences in their effectiveness and safety in treating onychomycosis. Evans and Sigurgeirsson (1999) found that terbinafine had a higher mycological cure rate (70.6%) than itraconazole (62.8%) in real-world practice. Bräutigam (1998) demonstrated that terbinafine achieved a significantly higher cure rate (81% vs. 63%) and faster time to negative culture than itraconazole. These findings are particularly important for podiatrists managing severe infections, as terbinafine offers a more reliable cure and faster recovery. However, safety concerns cannot be overlooked. Etgü (2023) reported higher rates of elevated liver enzymes in patients treated with terbinafine (8.4% for ALT and 5.2% for AST), compared to itraconazole.

In conclusion, terbinafine’s superior efficacy, faster action, and higher patient satisfaction make it the first-line oral medication treatment for onychomycosis, but careful patient selection and monitoring is essential to mitigate the risk of liver toxicity. Based on the incidence of onychomycosis in the elderly (Gupta et al., 2022), podiatrists need to exercise caution when prescribing terbinafine to elderly patients due to the increased risk of hepatotoxicity associated with this medication. Elderly patients, who are more vulnerable to drug-induced liver injury due to age-related physiological changes, reduced liver function, alteration in hepatic mass and blood flow and potential polypharmacy need special consideration when considering the choice of medication (Mitchell & Hilmer, 2010). Given these risks, careful monitoring of liver enzymes before and during terbinafine treatment is essential for all patients but especially for elderly patients. Conducting baseline liver function tests and scheduling regular follow-ups can help detect early signs of hepatotoxicity, allowing podiatrists to adjust treatment promptly if needed. Furthermore, for patients with pre-existing liver conditions or those on other hepatotoxic medications, oral itraconazole or topical treatments may be safer alternatives.

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