A Rare Case of Actinomycetoma In Pregnancy: Effective Treatment with the Combination of Amoxicillin-Clavulanic Acid

Abstract

Introduction

Actinomycetoma is a chronic granulomatous of the skin and subcutaneous tissue caused by filamentous bacterial infection. In pregnancy, this disease is associated with poor clinical outcomes and often unresponsive to standard therapy. Although actinomycetoma is primarily treated with antibiotics, nevertheless, many recommended antibiotics cannot be used during pregnancy due to the potential for fetal harm. Report of actinomycetoma in pregnancy are infrequent. The management of mycetoma in pregnancy requires special attention in various aspects, particularly regarding the safety of the mother and fetus.

Case Presentation

A 21-year-old pregnant woman, gestational age of 31–32 weeks, presented with tumefaction, multiple nodules, and sinuses that secreting serosanguinolenta exudate on the right knee. The patient was diagnosed as actinomycetoma according to clinical manifestations of tumefaction, sinuses, and the appearance of grain from direct microscopic and histologic examination. Bacterial culture revealed the growth of Actinomycetes colony. The patient received amoxicillin-clavulanic acid 625 mg thrice daily. Clinical improvements were observed after the fourth week of therapy. There was no adverse event reported during the treatment period nor the follow up period.

Conclusion

Actinomycetoma in pregnancy has limitation in the choice of therapy. The combination of amoxicillin-clavulanic acid can be considered as an effective and relatively safe therapy for pregnancy with actinomycetoma.

Introduction

Mycetoma is a chronic, localized granulomatous infection of the skin and subcutaneous tissue, which can be caused by fungi (eumycetoma) or filamentous bacteria (actinomycetoma).¹ The clinical characteristics of mycetoma include a triad of symptoms: painless swelling (tumefaction), the presence of draining sinuses, and exudate from skin lesions containing grains.^1,2 Since 2016, mycetoma has been designated as a neglected tropical disease by the World Health Organization (WHO).² Globally, actinomycetoma accounts for 60% of all mycetoma cases and is frequently found in countries across North America, South America, and several nations in Asia.³ Actinomycetoma is caused by saprophytic organisms from soil or plants, with the most common pathogens being species from the genera Nocardia, Actinomadura, and Streptomyces.⁴ These organisms can enter the body through wounds or damaged skin barriers. The most common site of skin lesions is the lower extremities.⁴ Actinomycetoma is more frequently observed in males than females and can affect individuals of all ages, particularly young adults aged 20–40 years.^4,5

Actinomycetoma during pregnancy is associated with poor clinical outcomes⁶ and suboptimal therapeutic responses.^4,7 However, the prevalence of actinomycetoma during pregnancy remains extremely rare globally, and to date, no case reports of actinomycetoma in pregnancy have been documented in Indonesia. The primary treatment for actinomycetoma remains the administration of antibiotics, either as monotherapy or in combination, depending on the severity, dissemination, and location of the lesions.⁷ Treatment and management of actinomycetoma during pregnancy require special attention, particularly in the selection of systemic therapies that are effective yet safe for both the mother and fetus.⁴ This case report aims to describe a rare instance of actinomycetoma in a pregnant woman, highlighting the clinical presentation, diagnostic process, and successful treatment using oral amoxicillin–clavulanic acid. This report hopefully can offer practical insight into managing actinomycetoma during pregnancy, especially when treatment options are limited due to concerns about medication safety for the fetus.

Case Presentation

A 21-year-old pregnant woman with a gestational age of 31–32 weeks, came with a chief complaint of multiple skin-colored nodules that discharged yellowish fluid and blood, with swelling and pain on the right knee. The skin lesions first appeared four months prior to consult as few skin-colored nodule on a pre-existing scar on the right knee. The nodule was the size of a mung bean, firm to palpation, and painless. The nodules then enlarged and multiplied, and some draining sinus was developed. The right knee also showed progressively worsening in swelling. Approximately three years before the skin lesion appeared, the patient had a history of traffic accident causing some laceration on her right knee. For her complaint, the patient had sought treatment from a surgeon, but there was no improvement of her condition.

On physical examination, the vital signs and nutritional status were within the normal limit. Dermatological examination showed a tumor with multiple nodules and sinuses that discharge serosanguineous exudate, on the right knee (Figure 1a–d). Direct microscopic examination of the exudate from the sinuses using a 10% KOH solution revealed the presence of yellowish-white grains (Figure 2a), which is the characteristic of actinomycetoma. However, Gram staining did not demonstrate Gram-positive filamentous bacteria (Figure 2b). Ziehl-Neelsen staining showed no evidence of acid-fast bacilli (AFB) (Figure 2c), thereby ruling out mycobacterial involvement.

Figure 1.

Clinical presentation of the patient. Skin lesions prior to therapy (a–d). Skin lesions showed improvement after three months of treatment with amoxicillin-clavulanic acid (e–h).

Figure 2.

Results of direct microscopic examination. The 10% KOH preparation revealed the presence of grains ((a), red arrow). Polymorphonuclear (PMN) cells and Gram-positive cocci bacteria were observed on Gram staining (b). No acid-fast bacilli (AFB) were detected on Ziehl-Neelsen staining (c).

Histopathological analysis revealed fibrous connective tissue interspersed with inflammatory cells, predominantly lymphocytes and neutrophils. Sulfur granules were identified in multiple regions, surrounded by dense lymphocytic and neutrophilic infiltration (Figure 3a and b). Additionally, multinucleated giant cells and suppurative granulomas were observed, indicative of a chronic granulomatous inflammatory response. Periodic acid-Schiff (PAS) staining was negative for fungal hyphae or spores, thereby excluding eumycetoma as a differential diagnosis. Furthermore, Fite-Faraco staining was negative, reinforcing the exclusion of acid-fast bacterial infections. Culture of the exudate under anaerobic conditions at 25°C demonstrated the growth of Actinomycetes colonies on Sabouraud Dextrose Agar (SDA). The colonies were white to cream-colored, chalky, wrinkled, and rough-textured (Figure 3c–f). Microscopic examination of the cultured colonies revealed branched filamentous structures, consistent with the morphology of actinomycetes.

Figure 3.

Results of supporting examinations. Histopathological examination revealed the presence of sulfur granules ((a and b), green arrows) surrounded by lymphocytes and massive neutrophils ((b), red box). Culture examination showed the growth of filamentous bacterial colonies (c and d). Colonies of Actinomycetes were observed (e and f).

The patient was diagnoses as actinomycetoma, and was given combination of amoxicillin-clavulanic acid at a dosage of 625 mg three times daily for three months, which is safe to be given in pregnancy. Clinical evaluations were performed every two weeks. Clinical improvement was observed after three months of therapy, with wound healing resulting only in hyperpigmented macules, atrophic scars, and hypertrophic scars (Figure 1e–h). The patient reported no complaints or side effects during the course of the prescribed medication.

Discussion

Mycetoma, also known as “Madura Foot”, has been reported in several countries across Asia, including the Philippines, Japan, Sri Lanka, and Thailand, but the incidence of mycetoma in Indonesia has not been clearly documented. The microorganisms responsible for actinomycetoma enter the body through wounds or trauma to the skin, where they inoculate and proliferate in the subcutaneous tissue.¹ The incubation period for mycetoma ranges from 20 to 30 years after skin barrier damage.⁸ Microbial proliferation can occur more rapidly under conditions of malnutrition and immunosuppression,^7,9 including during pregnancy.^1,6,7,9

Cases of mycetoma in pregnancy are still rarely reported.^10,11 There have been only four reported cases, all of which showed clinical deterioration, with two involving bone destruction and one requiring amputation.¹⁰ This is believed to be due to cellular immune suppression mechanisms influenced by hormones during pregnancy.^4,10 Elagab et al¹² stated that a T-helper (Th)2 cytokine profile is associated with a more significant clinical severity or progression of mycetoma lesions. The shift from Th1 to Th2 immunity during pregnancy is a protective mechanism for fetal development, but it may increase the susceptibility of pregnant women to certain infections, including mycetoma.^6,7 In this case, the patient’s pregnancy may have been a risk factor that shortened the incubation period and led to rapid progression of symptoms, with lesions emerging three years after trauma and deteriorating within four months.

The diagnosis of mycetoma is established based on the clinical triad of symptoms: tumefaction, the presence of sinuses, and purulent or seropurulent exudate containing grains.^1,2 Exudate from the sinus openings containing grains is a hallmark sign of mycetoma.⁹ Grains are microcolonies of the causative organisms within the tissue and can be identified through macroscopic and microscopic examination of exudate, fine needle aspiration, or tissue biopsy.^1,9 Microscopic examination is performed by adding a 0.9% NaCl solution or 10–20% KOH solution to the exudate that spontaneously drains from the sinuses or through pressure on the sinus.⁹ The causative organism can be identified by evaluating the shape, color, and size of the grains.¹ In this case, microscopic examination with 10% KOH solution on exudate from the sinus revealed yellowish-white grains.

Histopathological examination of actinomycetoma reveals a suppurative reaction characterized by the presence of numerous polymorphonuclear cells (PMNs), fibrosis, neovascularization, and occasionally tuberculoid granulomas.^1,12,13 Infections caused by Nocardia exhibit characteristic granules with diameters ranging from 30–200 µm, which are partially basophilic to amphophilic and surrounded by radially arranged eosinophilic material, known as the “Splendore-Hoeppli” phenomenon.^1,13,14 Granules of Actinomadura madurae appear smoother and larger, with diameters of 1–3 mm, purple in color, and have a cartographic (map-like) pattern with eosinophilic edges.¹ Granules of A. pelleteri are dense, reddish, and measure 200–500 µm in diameter, while granules of Streptomyces somaliensis are spherical, firm, pale, and range in size from 1.5–10 mm.^2,14 Special stains, such as PAS, can be used to rule out eumycetoma by identifying the absence of chlamydospores or hyphae.¹⁵ The Fite-Faraco stain which is designed to detect acid-fast bacilli (AFB), may occasionally show positivity in Nocardia, a partially acid-fast organism.³

In this case report, histopathological findings included fibrous collagenous connective tissue infiltrated by lymphocytes and neutrophils. Sulfur granules surrounded by massive lymphocytic and neutrophilic inflammatory cells were observed in some areas. Additionally, multinucleated giant cells and suppurative granulomas were identified. PAS staining revealed no hyphae or spores, thereby excluding the diagnosis of eumycetoma. Fite-Faraco staining was negative for AFB. These histopathological findings support the diagnosis of actinomycetoma in this patient.

Fungal and bacterial culture examination of grain preparations can accurately and specifically identify the causative species of mycetoma.⁹ The media commonly used for the growth of microorganisms causing actinomycetoma include Sabouraud dextrose agar, Lowenstein-Jensen agar, thioglycolate broth, Columbia agar, and brain heart infusion (BHI) agar.^2,16 In this patient, the culture specimen, consisting of exudate from the sinus, was inoculated on Sabouraud dextrose agar, resulting in the growth of Actinomycetes colonies.

The management of actinomycetoma is determined based on the etiology, location, extent of skin lesions, and severity of the disease.^1,2 Antibiotics can be administered as monotherapy or in combination. Combination therapy aims to prevent resistance and aid in eradicating residual infection.^1,17,18 To date, there are no established guidelines for antibiotic therapy in actinomycetoma. Several antibiotics reported for the treatment of actinomycetoma include streptomycin, dapsone, cotrimoxazole, rifampicin, and amikacin.^1,18

The management of mycetoma during pregnancy requires consideration of various aspects, particularly the well-being of both mother and the fetus.^4,7 Most antibiotics commonly used for actinomycetoma are not recommended during pregnancy due to potential risks to the fetus. Amoxicillin-clavulanic acid is the primary antibiotic therapy of choice for pregnant women,¹ classified as generally safe for use.¹⁹

A study by Bonifaz et al⁵ involving 21 patients with actinomycetoma treated with amoxicillin-clavulanic acid demonstrated clinical and microbiological cure in 70% of cases. The duration of therapy varied, with an average treatment period of ten months. Patients with bone and internal organ involvement exhibited slower therapeutic responses compared to others.²⁰ An in vitro study revealed that amoxicillin-clavulanic acid at a dose of 500 mg/125 mg orally for 3–6 months had an inhibitory effect of up to 97% against the genus Nocardia.²¹ In an animal model, the combination of amoxicillin-clavulanic acid and linezolid showed better synergistic effects.²¹ However, linezolid could not be administered to the patient in this case report, as it is not recommended during pregnancy (category C).²⁰

In general, 60–90% of actinomycetoma cases respond well to antibiotic therapy.^1,14 Actinomycetoma is considered cured when there is no longer any clinical activity or symptoms of the disease, no grain is detected, and culture results are negative.¹ Discontinuation of therapy can be considered if there is a reduction in lesion volume, closure of sinuses, negative culture results for three consecutive months, evidence of bone regeneration on radiographic examination, and no grains are found.^12,14

The patient received antibiotic treatment for three months and showed a good therapeutic response, with wound healing resulting in hyperpigmented macules, atrophic scars, and hypertrophic scars. Although most cases of actinomycetoma respond well to long-term antibiotic therapy, periodic monitoring is necessary due to the ongoing risk of recurrence. In this case, the patient was followed up for six months, including the postpartum period, after achieving clinical improvement. No signs of recurrence were observed during this period, indicating a sustained therapeutic response to oral amoxicillin–clavulanic acid. Although this case showed good clinical response without recurrence, it is important to remain cautions regarding the potential for antimicrobial resistance, particularly to amoxicillin–clavulanic acid. While no resistance was detected in this patient, resistance among Actinomycetes species has been reported in other settings.

Conclusion

Actinomycetoma during pregnancy is associated with poor clinical outcomes and reduced responsiveness to standard therapy. Accurate diagnosis and appropriate management of actinomycetoma during pregnancy require special attention to ensure the safety of both the mother and the fetus.

Funding Statement

The authors received no specific funding for this work. Open access funding provided by University of Padjadjaran.

Ethics Approval and Consent to Participate

This study has obtained ethical clearance from the Research Ethics Committee of Dr. Hasan Sadikin General Hospital No. DP.04.03/D.XIV.6.5/38/2025.

Consent Statement

Written informed consent was obtained from the patient for publication of this case report and the accompanying images. Approval has been obtained from Dr. Hasan Sadikin General Hospital to publish the case details.

Disclosure

The authors report no conflict of interest in this work.