Challenges in Managing Treatment-Resistant Mpox Complicated by Severe Superinfection

Abstract

Though typically self-limiting, severe mpox infections have been treated with antiviral medications, most notably tecovirimat. Various reports exist of mpox progression despite tecovirimat treatment. Treatment resistance can be due to acquired mpox strain mutations, most often occurring in an immunocompromised host. We present the case of a male with AIDS who developed disseminated treatment-resistant mpox infection complicated by superimposed bacterial and fungal infections. His orthopoxvirus polymerase chain reaction result remained positive despite treatment with 4 weeks of oral tecovirimat and 3 doses of intravenous cidofovir. Poor response to antiviral therapy was likely due to his underlying immunocompromised state; however, strain resistance cannot be ruled out given that the patient had started but not completed a 14-day course of tecovirimat 8 months prior, at the time of initial mpox diagnosis. Patients with mpox who are immunocompromised may require extended and additional treatment beyond the standard 14 days of tecovirimat, such as cidofovir, brincidofovir, or intravenous vaccina immune globulin.

Mpox, an orthopox DNA virus, has been implicated in sporadic outbreaks in Africa since the 1970s, with the most recent surge affecting the United States beginning in May 2022. The majority of cases, up to 98%, occur in gay or bisexual men, with the most common suspected mode of transmission being sexual contact [1]. Roughly 40% of infections occur in individuals with HIV infection. The most common presentation is skin lesions with a nonspecific prodrome of fever, fatigue, and lymphadenopathy [1, 2]. Cutaneous manifestations typically begin as an umbilicated papule or vesicle with progression to a crusted scab [2]. Most cases are mild and self-limited, with a minority of patients requiring hospitalization for treatment of pain and/or bacterial superinfection [1]. An even smaller percentage of patients require antiviral treatment: in one study, 5% of 528 patients with mpox were treated with cidofovir or tecovirimat [1]; in another, 17.6% of 250 hospitalized patients required treatment with tecovirimat alone [2].

Tecovirimat—initially approved for the treatment of smallpox, another member of the orthopoxvirus family—has been trialed against mpox, although no randomized clinical trials exist to robustly demonstrate its efficacy against this particular orthopoxvirus. Tecovirimat, which can be given orally or intravenously, inhibits activity of the orthopoxvirus p37 protein, which is involved in the release of the enveloped virus [3]. Cidofovir, a DNA polymerase inhibitor that works by slowing viral DNA replication, has also been proposed as a potential mpox treatment but is available only parenterally given its poor oral absorption. Though approved by the Food and Drug Administration for the treatment of cytomegalovirus retinitis, cidofovir has broad activity against many DNA viruses, unlike tecovirimat, which has activity against only orthopoxviruses [4]. One study suggested a synergistic in vitro and in vivo effect of tecovirimat and cidofovir when used concurrently to treat cowpox virus, an orthopoxvirus, in mice [5]. Moreover, cidofovir carries a dose-limiting nephrotoxicity, which may be partially mitigated by concurrent administration of probenecid, and is thus contraindicated in patients with a serum creatinine level ≥1.5 mg/dL [4]. Given tecovirimat's more favorable side effect profile and increased specificity for orthopoxviruses, the World Health Organization developed an emergency use protocol recommending 14 days of oral tecovirimat for treatment of severe mpox infections [6].

CASE PRESENTATION

A 34-year-old male presented to the emergency room with chronic diffuse cutaneous wounds. He had a medical history of untreated mpox, AIDS (CD4 count, 105 cells/mm³) poorly adherent to antiretroviral treatment, cytomegalovirus colitis status post colostomy, hypertension, and treated syphilis.

He was initially diagnosed with mpox 8 months prior to this admission. At that time, he presented with diffuse, painful, cutaneous lesions on his face, chest, back, bilateral legs, and scrotum in the setting of uncontrolled AIDS (CD4 count, 49 cells/mm³; Figure 1). He was poorly adherent to his antiretroviral therapy, including bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) and trimethoprim/sulfamethoxazole prophylaxis. The infectious disease division was consulted, and the Department of Health was notified of the positive orthopoxvirus polymerase chain reaction (PCR) result. PCR samples were collected by swabbing the cheek lesions. He started a 14-day course of tecovirimat (600 mg, twice a day, by mouth) but left against medical advice (AMA) on day 3 of the regimen. He was readmitted 4 days later and given 3 additional doses of tecovirimat before leaving AMA again. Completion of the tecovirimat course could not be verified with the patient, and it was assumed that the course was not finished as prescribed. During the following 8 months, he was admitted to our institution and multiple neighboring hospitals for pain control and antimicrobial treatment of new progressing wounds associated with fevers and purulent discharge. One month before admission, he completed the full 14-day tecovirimat course (600 mg, twice a day) at an outside hospital. During that admission, the result of his orthopoxvirus PCR, sampled by swabbing the hand lesion, remained positive.

Figure 1.

Initial monkeypox presentation: primary lesions. Annular lesion with hemorrhagic crust on the scrotum (left), left mandible (center) and right perioral area (right).

During this most recent admission, he presented with tender wounds, particularly on the right hand, foot, and head (Figure 2). Admission laboratory values were significant for elevated inflammatory markers, including a C-reactive protein level of 29.40 mg/L (reference range, 0.10–2.80) and an erythrocyte sedimentation rate >136 mm/h (reference range, 0–15) with a normal white blood cell count of 8.06 × 10³/µL (reference range, 4.5–11 × 10³), CD4 count of 105 cells/mm³, and HIV viral load of 901 copies/mL.

Figure 2.

Admission (Hospital Day 1). Wounds on admission due to secondary bacterial/fungal infections including fungation ulcerated plaque on the right palm with verrucous borders (left), scaring alopecia with crust on the scalp (center), and hyperkeratoic plaque with weeping crust on the right plantar foot.

The orthopoxvirus PCR test result remained positive, and he restarted oral tecovirimat (600 mg, twice a day) for disseminated mpox infection. Out of concern for tecovirimat resistance given a previously incomplete course and persistently positive PCR test result, he also started cidofovir with intravenous fluids and probenecid for nephroprotection. He was given once-weekly intravenous cidofovir (5 mg/kg, 315 mg) for 3 weeks. During his hospitalization, pain management was accomplished with hydromorphone, pregabalin, acetaminophen, and methocarbamol. For his HIV, he continued taking Biktarvy and trimethoprim/sulfamethoxazole.

Wound cultures during the admission grew multidrug-resistant Pseudomonas, Enterococcus faecalis, and Candida auris; he was treated with linezolid (600 mg, twice a day), ceftolozane-tazobactam (3000 mg, 3 times a day), and micafungin (200 mg, every day) for 4 weeks. Blood cultures were unremarkable with no growth, and magnetic resonance imaging of the hand was negative for osteomyelitis. He underwent debridement and punch biopsy of the right hand, demonstrating evidence of acute and chronic inflammation without transformation to squamous cell carcinoma, as well as negative herpes simplex virus and spirochete stain results. Grocott methenamine silver stain showed rare fungal hyphae. His wounds gradually improved with antibacterial and antifungal treatment (Figures 3–5); however, orthopoxvirus PCR findings remained positive 2 weeks after discharge despite prolonged antiviral treatment.

Figure 3.

Hospital day 12. Progession of wounds after two weeks of micafungin, linezolid, and ceftolozane/ tazobactam, but prior to staring tecovirimat/ cidofovir while awaiting emergency use investigational drug approval, fungating ulcerated plaque on the right palm (left), scaring alopecia on the left scalp with annular crusted lession (center), and macerated plaque on the right plantar foot (right).

Figure 5.

One month after completion of tecovirimat/ cidofovir treatment. Superficial erosion with crust on right palm (left), erythematous eroded plaque on the left mandible (center), and mamilated, eroded plaque on right planter foot (right).

Figure 6.

Timeline of antibiotic/ antifungal/ and anitiviral therapy. Only medications given for greater than one week are included (empiric medication prior to speciation results not listed). HD indicates hospital day number. *C indicates cidofovir administration.

The patient was discharged home with wound care supplies, pain medication, Biktarvy, and trimethoprim/sulfamethoxazole, given the CD4 count <200 cells/mm³ at the time of discharge. One month after discharge, the patient reported persistent pain and discomfort despite compliance with antiretroviral medications and trimethoprim/sulfamethoxazole prophylaxis. Per chart review of updated photos, his wounds appeared to have improved at 1 month postdischarge (Figure 4).

Figure 4.

Hospital Day 39. Status post four weeks of antibiotics/ anfifungal and tecovirimat/ cidofovir, and hand debridement. Macerated ulcerated plaque on the right palm (left), ulnar side of the right hand (center), and planter surface of the right foot (right).

DISCUSSION

A significant challenge in treating this patient was the persistently positive orthopoxvirus PCR result over the course of 10 months, despite prolonged treatment with tecovirimat and cidofovir, suggestive of a protracted infection rather than a reinfection. Given the patient's history of incomplete tecovirimat treatment, it is possible that this was due to acquired strain resistance to tecovirimat. While the patient's particular viral strain was sent to the Centers for Disease Control and Prevention, this information is not available to the general public, as it is under investigation; thus, there is no definitive proof of tecovirimat resistance.

There are few documented cases of confirmed tecovirimat resistance, with sequencing data demonstrating variation throughout several single-nucleotide polymorphisms [7–9]. Nearly all cases documenting tecovirimat resistance occur in patients who are immunocompromised, most due to advanced HIV infection [9, 10]. In addition, cases of tecovirimat resistance have been associated with protracted infections requiring multiple courses of tecovirimat treatment [8]. Still, the theoretical risk of tecovirimat resistance remains high, given that single-nucleotide polymorphisms within VP37 can render the drug ineffective, thereby questioning the efficacy of tecovirimat monotherapy in patients with mpox infections who are severely immunocompromised, particularly those who have already received this treatment. For this reason, the low barrier to resistance is mentioned in the drug label [8].

This patient's inability to clear the mpox virus was likely due to his weakened immune system, a result of his poorly controlled AIDS. It has been demonstrated that patients with advanced HIV (CD4 count <200 cells/mm³) infected with mpox are more likely to develop a severe, disseminated, and necrotizing form of the virus [11]. His persistently positive mpox serology results and improvement in CD4 count from 49 cells/mm³ at the time of initial mpox diagnosis to 105 cells/mm³ at the time of presentation demonstrate weakened but not completely lacking immune system functioning. Decreased oral intake is another potential etiology for our patient's treatment failure, as oral tecovirimat requires fatty meals for absorption. Given our patient's decreased oral intake secondary to depressed mood, treating with intravenous tecovirimat was discussed but ultimately not implemented.

Although robust data are lacking on the efficacy of antivirals against mpox, only a minority of patients require this medical treatment. The Centers for Disease Control and Prevention's expanded access protocol recommends tecovirimat for individuals with severe disease or individuals who are immunocompromised and at higher risk of developing severe disease from monkeypox. Other potential treatment options include cidofovir and VIG-IV, which have been trialed in cases clinically resistant to tecovirimat. Brincidofovir, an oral prodrug of cidofovir, has been approved for the treatment of smallpox with decreased risk of nephrotoxicity, increased potency, and oral dosing as advantages over cidofovir [4, 12, 13]. Topical cidofovir 1% has been investigated as a potentially beneficial therapy to bypass the systemic toxicities of cidofovir in patients with mild skin lesions [14]. Given the extensive bacterial infections that overtook his primary mpox lesions, topical antiviral treatment would likely not have been effective in our patient. Various combinations of antivirals that have been trialed in the treatment of mpox are detailed in Table 1 [7, 15–19]. Finally, antiviral treatment should be supplemented with supportive care, including pain control, psychological support, and wound care. Moist occlusive dressings can promote re-epithelialization for patients like ours with ulcerative or erosive lesions.

Table 1.

Antiviral Treatments Utilized in Other Cases of Protracted Mpox Infections

Clinical Case	Treatments Prior to Admission	Treatments During Current Admission	Outcome	Reference
36-y-old male with HIV; CD4 count, 122 cells/mm3	None	2 doses of IV cidofovir, 5 mg/kg	Mpox PCR negative result with clinical improvement 21 d after diagnosis	Fabrizio et al (2023) [18]
48-y-old male with HIV; CD4 count, 27 cells/mm3	2 wk of tecovirimat	19 d of tecovirimat (second course) 3% topical cidofovir Three doses of IV cidofovir 5 mg/kg	Persistently positive mpox PCR result but improved clinically	Stafford et al (2023) [17]
49-y-old male with HIV; CD4 count, 218 cells/mm3	2 wk of tecovirimat 2 wk of tecovirimat (second course)	30 d of tecovirimat (third course) 3 doses of IV cidofovir, 5 mg/kg 2 doses of IV vaccinia immune globulin, 9000 U/kg	Clinical improvement with near complete resolution of lesions	Martinez et al (2023) [16]
23-y-old male with HIV; CD4 count, 173 cells/mm3	None	3 wk of tecovirimat 4 doses of IV cidofovir, 5 mg/kg	Persistently positive mpox PCR result; patient died of septic shock	Caria et al (2023) [15]
53-y-old male with HIV; CD4 count, 200 cells/mm3	None	4 wk of tecovirimat	Mpox PCR negative result with clinical improvement	Bruno and Buccoliero (2023) [13]
21-y-old male with Hodgkin lymphoma receiving chemotherapy	None	28 d of tecovirimat 2 doses of IV cidofovir, 5 mg/kg 1 dose of IV vaccinia immune globulin	Complete clinical recovery with eventual resumption of chemotherapy.	Dammann et al (2023) [19]

Abbreviations: IV, intravenous; PCR, polymerase chain reaction.

The final challenge of this case was managing his bacterial and fungal secondary infections, which posed more significant morbidity than the primary viral infection. These infections also complicated the clinical picture, as it was difficult to discern if his wounds were reflective of hypertrophic verrucous mpox, which has been described as a sign of disease progression, or appeared so clinically due to the secondary infections [11, 12]. The severity of these infections was attributed to a combination of incomplete antimicrobial treatment due to recurrent discharges AMA and the patient's underlying AIDS. It was also unknown if he adhered to home wound care recommendations, as the damaged skin barrier caused by primary mpox lesions created a nidus for these secondary infections. Since mpox infection is commonly comorbid with HIV, patients with AIDS or other immunocompromising conditions or medications should be more closely monitored for superimposed skin and soft tissue infections. The prevalence of secondary bacterial infections in patients with mpox ranges from 19% of all patients [20] to 58% among hospitalized patients [21], suggesting a potential role for antimicrobial prophylaxis for certain patients with severe mpox, particularly those who are immunocompromised.

While typically self-limited, sequelae of disseminated mpox include secondary infections, sepsis, and encephalitis. Under expanded access protocols, tecovirimat is available for patients with, or at risk of developing, severe disease. Still, patients with mpox can respond poorly to tecovirimat due to primary or secondary immunodeficiencies, strain resistance, or poor oral absorption. In these cases, intravenous cidofovir, oral brincidofovir, or intravenous vaccinia immune globulin can be trialed. Patients with limited disease can be managed with pain control and wound care alone or potentially with topical cidofovir pending additional studies.

Notes

Patient consent statement. The patient's written consent was obtained.