Casuistics: Cure of a treatment resistant (Terbinafine, Ciclopirox)
Tinea corporis (ringworm) by time controlled additional application of 3% hydrogen
peroxide (H2O2) and 1% formaldehyde solutions
Summary: Broadband antimycotics like Terbinafin or Ciclopirox inhibit important metaboliic pathways in fungal cells, like cell wall synthesis or the spore protecting enzyme catalase as defense against oxidative agents like hydrogen peroxide (H2O2). Resistence against these drugs is increasingly observed.
Time controlled application of 3% H2O2 followed by 1% formaldeyde solutions at 15 and 10min prior to the next Ciclopirox/Terbinafin standard therapy every 12 or 24h overcomes resistance. H2O2 damages the Ciclopirox inhibited catalase of spores and formaldehyde binds to free aminogroups of amino acids in spore and keratin proteins of skin cells thus harming simultaneously spores as well as fungus cells and their keratin food. This curative therapy shortens treatment time considerably (half) as opposed to the the additional H2O2 treatment alone. No relapses were observed. The fast reaction of both reagents within seconds or a few minutes does not detectably harm the subsequently applied antimycotic drugs
Prior History: German brown goats were kept since 1993 all year round in an open shack with straw covered ground on a meadow of around 1ha until death from age. Dry straw was delivered for many years as 15-20 kg square bales and since 2017 as 300-400kg round bales being wet in in the lower 15% of their diameter due to storage on a weather exposed meadow. Humidity remained for several monthe even during dry storage due to high pressure packing of the straw. The goats developed afterwards from time to time bald skin areas of 5-8 cm diameter although only dry straw was sprinkeled. The lesions corresponded clinically to a Trichophyton tonsurans fungal infection disappearing after 3-4 applications of Micocept (Miconazol 1%) Shampoo being applied to the affected skin and around 5cm into the healthy appearing pelt with single use nitril gloves. This cured the symptoms within two weeks (hair regrowth).
The last animal (12 years old) showed a massive and progressive general hair loss in November 2020. Miconazol shampoo had no effect and the animal died after around a week from the initially observed hair loss with paralysis of the hind legs.
Human Infection: The female patient (healthy, hard working, body mass index (BMI) 21.5 and without records of earlier Trichophyton fungus infections) used the rubber boots of the goat stable the next time in March 2021 for snow shoveling. The leg part of the working cloths as well as the non washable artificial fur within the boot shafts became wet during this work. About 14 days later painful and strongly itching 3-4cm measuring lesions with elevated red points appeared on both lower legs about 10cm below the patella at the height of the boot shafts. The lesions enlarged from day to day (fig.1 left)
Initial treatment (Mar-Mai 2021): The supposed fungal infection was treated for about 3 weeks with Lamisil (Terbinafine 1%) and Batrafen (Ciclopirox 1%) ointments mornings and evenings. Pain and itching diminished but the lesions continued to increase in size. The university dermatology hospital was consulted early Mai. Some of the brownish, reddish surface material of the lesions was scraped off for culture. The prescibed cortison ointment Infectocortisept (Halometason 0,5mg/g, Triclosan 1%) was administered with unprotected hands, assuming a non infectious excema after the unsuccessful antimycotic treatment. Lesion redness diminished significantly after 3 days but there was an increase in size until the follow-up visit 3 weeks later. Cortisone improves the inflammatory condition, weakens the local immune defense and can mask the cause of the lesions in case of fungal infections (1).
Itching on the lateral sides of both arms appeared approximately two weeks later, accompanied by the formation of reddish areas 2 days after exhaustion of the cortison ointment (14 days). This was in favor of a fungal self infection by contact with the unprotected palmar surfaces of the hands after application of the antimycotic ointment to the lower leg, ressembling clinically Trichophyton (T.) rubrum growth. It was accompanied by painful swellings of the front parts of both Musculi (M.) deltoidei, M.brachioradialis and M.tibialis anteriores causing walking difficulties. Lamisil alleviated itching and pain to some extent without reducing lesion size for the remaining time until the follow-up visit. Batrafen and Duogalen (Flumetasonpivalat 0,2mg/g, Triclosan 3%) ointments were prescribed to reduce fungal infection and inflammation at negantive fungus cultures.
Increased Hygiene: The ointments were rubbed in with single use nitril gloves. Knee highs and long sleeved cotton underwear shirts were used to minimize fungus spread. These clothings were daily changed (washing: knee highs at 40C with desinfecting washing powder, cotton shirts at 65C, cotton bedclothes weekly at 95C). Water was absorbed by paper towels after body washing to avoid infestation of towels with desquamated fungal spores. This was efficient because no infection of other family members occurred during the entire treatment.
Further Development of treatment (Jul-Dec 2021): Duogalen was only used to calm strong itching to avoid changes of skin structure. Batrafen and Lamisil were applied in the morning, at noon, in the evening and once during the night. Itching and pain was lowered but the lesions were still growing. The treatment prevented efficiently the formation of open lesions by scratching. The alternating additional administration of Daktar (Miconazol 2%) or Canesten (Clotrimazol 1%) cremes between the application of the other ointments was without effect during a two week period concerning lesion size. treatment was continued with Batrafen and Lamisil in the morning and evening supplemented by systemic Terbinafine (250mg, once a day). The lesions stopped growing and a relief of symptoms was observed without diminution of lesion size. Loss of hair and general weakening occurred after 4 weeks of treatment making it difficult to climb the stairs to the 1st floor of the house, phenomena that had never been observed before. As a consequence, systemic treatment was stopped after five weeks. The observed well known side effects of Terbinafin treatment were fully reversible.
At this point it was clear that systemic Terbinafine in conjunction with topic Terbinafine and Ciclopirox calmed symptoms but were unable to efficiently eliminate fungus growth. Terbinafine acts by inhibition of fungal cell wall synthesis (2), while Ciclopirox chelates Fe3+ ions (3), thus inhibiting the action of several important biomolecules amongst them the hydrogen peroxide (H2O2) degrading katalase of fungal spores (4). Fungal spores are sensitive to oxidation without catalase protection. Reactive oxygen molecules like H2O2, O2- od OH. produced by tissue macrophages or granulocytes can inactivate fungal spores in tissues but the mechanisms were not sufficietly strong in this case.
Affected skin areas were from now on twice consecutively wiped with 3% H2O2 solution (H2O2, around 1M, food quality without stabilisors) initially 30min after Lamisil and Batrafen application using a swab of paper kitchen towel twice lengthwise and once transversly folded. It was imbibed with approximatly 3ml H2O2 solution prepared in 100ml quantities by 1+3 dilution with deionized water from the 12% commercial stock solution (S3 Chemicals, Göttingen, Germany). This was enough for 4 applications that is 2 days of treatment. Itching and prickling in the lesion areas disappeared with 15-20min. The redness of the lesions vanished within a few days but the lesion areas and the muscle remained nevertheless contact sensitive. The ointments were no yet fully imbibed into the skin at this time as evidenced by surface smear. It could be argued that H2O2 inactivates the antifungal substances by oxidation. A later application time point was therefore used in the final treatment scheme.
Two weeks of treatment with only twice a day 3% H2O2 application was not successful. Dose increase by wiping 3 or 4 times consecutively at the selected time points morning and evening may cause painful tissue irritations without noticeable effect on fungal lesions. Duogalen application and one day suspension of the H2O2 application eliminated the irritation.
With this, inhibition of fungus proliferation by Lamisil, inactivation of fungus spore catalase by Batrafen as well as of fungus spores by H2O2 oxidative action are of decisive importance for therapeutic success. H2O2 penetrates cell walls and tissues but not very far because the molecule is quickly degraded by cell catalases and does, as shown above, not inactivate fungal spores without spore catalase inhibition. Topical H2O2 application augments in this way the insufficient production of reactive oxygen molecules by inflammatory tissue cells in an efficient way.
Lesions were treated in a simplified treatment scheme with Lamisil and Batrafen twice a day (8am, 8pm) by covering lesions with around 2cm overlap into adjacent healthy appearing areas. 3% H2O2 solution was applied 10min prior to the next ointment application that is at still inhibited spore catalase. The skin was dry before the next ointment administration, excluding potential oxidation of antifungal molecules. Three months treatment made all symptoms disappear. treatment was continued another month for relapse prevention. Two weeks later initial symptoms of fungal regrowth were observed indicating a too short after treatment.
Successful treatment (Jan-Mai 2022): The simplified treatment (Jan-Mar) was resumed, all symptoms (lesions, swelling. pain. itching, prickling, contact sensitivity) had disappeared by the end of March. treatment was continued April and Mai with absent symptomes between June and September that is the infection is cured (fig.1 right).
Therapy iumprovement during second infection (Oct 2022): Wearing a pair of non desinfected (desinfection: crumpled kitchen towel sheet imbibed with 5ml 10% formaldehyde solution in each shoe and packed in a air tight plastic bag for 3 days, then 14 days aeration in open air) half high rubber boots resulted in lesions on both legs just above the ankles. The affected areas were treated as before with Ciclopiroxand Terbinafine every 12h preceded 15min before by 3% H2O2 and 5min kater by 1% formaldehyde solutions. H2O2 is consumed within a short time (30-60sec) by cell and tissue catalases. Formaldehyde blocks free amino groups of amino acids in proteins. This impairs fungus cell and spore functions as well as their keratin food in skin surface cells, similarly as higher formaldehyde concentrations used in anatomy or pathology for tissue fixation. Formaldehyde reacts within a short time (seconds to minutes) so no noticeable inactivation of the subsequently applied antimicytic molecules occurs. The second infection was overcome within 6 weeks therapy that is significantly faster than during the first treatment (12 weeks) without formaldehyde. Potential relapses were avoided by 4 weeks continuation of therapy with no signs of fungal infection for more than 6 months afterwards. Affected areas were weekly washed for skin cleaning and removal of remaining drug substances.Cancer risk: Longterm formaldehade inhalation may cause malignant nose and pharynx tumors or myeloid leukemia in bone marrow (5). Formaldehyde irritates the skin in concentrations above 5%, lower concentration only after several minutes of contact which is not given durng one or two short wipes with a folded and 1% formaldehyde imbibed kitchen towel swab. It is shortly inactivated by reaction with free amino groups or enzymatic action. The formation of malignant skin tumors by formaldehyde application has not been described.
Overshooting inflammation during the initial therapy period may result in transudation of small amounts of tissue fluid at inflammatory skin points due to local irritation by H2O2 and formaldehyde solutions, although their application on healthy skin during several weeks was non irritating. Antifungal therapy was continued in this case, while the application of H2O2 and formaldehyde solutions was omitted. Application of a corticoid ointment (Duogalen (Flumetasonpivalat)) for three days reduced inflammation, followed by H2O2 application for a week, priot to the resumption of treatment with combined H2O2 and formaldehyde solutions, as described.
Conclusions: In retrospect, a fungus strain was acquired from longtime humid wheat straw that was resistant against topical antifungal drugs (Terbinafine, Ciclopirox, Miconazol, Clotrimazol) as well as systemic Terbinafine treatment. It ressembled clinically a T. rubrum (Tinea corporis, ringworm) infection whose spread could be stopped by H2O2 oxidative damaging of fungus spores containing Ciclopirox inhibited catalase. Given that fungal cells typically produce spores under adverse conditions, the proposed appkication of 3% hydrogen peroxide solution 10-15min prior to Ciclopirox administration may also be useful for the oxidative elimination of spores from other dermatophytes.
The time controlled application of 3% H2O2 and 1% formaldehyd solutions represents a simple and efficient method to overcome increasing treatment resistence of Trichophyton fungus strains against antimycotics (6, 7, 8), in case the present treatment results can be generalized.
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