Management of difficult-to-treat Clostridioides difficile in a patient with chronic osteomyelitis

Abstract

A 61-year-old male patient being treated with intravenous antibiotics for left foot osteomyelitis presented to the hospital septic, with several days of worsening abdominal pain, bloating and watery bowel movements. Investigation revealed that the patient had severe, treatment-resistant Clostridioides difficile colitis. He was initially treated with oral vancomycin and intravenous metronidazole, which was switched to oral fidaxomicin. After no improvement in the patient’s symptoms, he was treated with two faecal microbiota transplants. He was offered a third faecal microbiota transplant but declined. The patient was placed back on oral fidaxomicin and saw ultimate resolution of his symptoms. This case provides an example of a treatment pathway for refractory C. difficile infection.

Background

Clostridioides difficile, a gram-positive, spore-forming bacteria that produces pathologic toxins, can colonise the intestinal tracts of patients taking antibiotics and cause C. difficile infection (CDI).¹ CDI can manifest from mild diarrhoea to severe disease with complications such as pseudomembranous colitis, toxic megacolon, sepsis and death.² Since 2000, the burden of disease caused by CDI among hospitalised adults has increased substantially around the globe, awarding C. difficile the most common cause of hospital-acquired diarrhoea in USA, Europe and worldwide.^2–5 The incidence of refractory and recurrent CDI also increased during this time.^{6 7}

Treatment of CDI is based on disease severity—non-severe, severe, fulminant and recurrent. Non-severe is classified by leucocytosis with a white cell count of less than 15 000×10⁹/L and a creatinine of less than 1.5 mg/dL; severe by leucocytosis of over 15 000×10⁹/L and creatinine of more than 1.5 mg/dL; fulminant by hypotension, shock, ileus or megacolon; and recurrent by symptom recurrence within 8 weeks of successfully completing treatment for CDI.⁸ In both non-severe and severe disease, a 10-day course of vancomycin or fidaxomicin is the treatment of choice.⁸ Vancomycin accompanied by intravenous metronidazole is the therapeutic option for patients with fulminant disease.⁸ For a first episode of recurrence, a prolonged tapered and pulsed vancomycin regimen or 10-day course of fidaxomicin should be used.⁸ For subsequent episodes of recurrence, the following should be considered: vancomycin in a tapered and pulsed regimen, a 10-day course of vancomycin followed by a 20-day course of rifaximin or a 10-day course of fidaxomicin.⁸ A faecal microbiota transplant (FMT) is indicated when a patient has failed the appropriate antibiotic treatment or experienced two episodes of recurrence, as FMT has the highest rate of prevention for recurrent CDI among all treatment options.^{8 9} FMTs are considered a novel approach that reconstitutes a diverse gut microbiome through multifactorial mechanisms.^10–12 In patients with complications such as megacolon, colonic perforation, acute abdomen or septic shock associated with organ failure, surgical intervention is recommended.⁸

Recent review of the literature reveals increasing failure of standard treatment for CDI and growing resistance to antimicrobials worldwide.¹¹ Studies investigating standard treatment reveal a 22.4% failure rate for metronidazole, a 14.2%–26.9% failure rate for vancomycin and a 12.7%–15.4% failure rate for fidaxomicin.^{7 12 13} Further, after the first episode of recurrence, fidaxomicin was found to have up to a 19.7% failure rate and vancomycin up to a 35.5% failure rate.¹⁴ Studies focusing on the efficacy of FMTs reveal 81.3%–84% resolution among refractory and recurrent CDI with a single procedure.^{15 16} This rate increases to 92%–93.8% when including repeated FMTs, suggesting consecutive courses have an incremental effect.^17–19 In a long-term follow-up study examining the efficacy of FMTs in refractory CDI in elderly individuals, a secondary rate of 95.9% was observed when follow-up treatment included a repeat course of vancomycin and/or repeat FMT after initial failure of FMT, suggesting improved medication response status post FMT.²⁰

Though FMTs improve the cure rate for refractory and recurrent CDI, a portion of the population is left affected. More data are needed to provide insight into the treatment course in these patients.²¹ In the following case report, we discuss a complex patient that fits this presentation and describe the course of treatment that allowed him to achieve symptom resolution.

Case presentation

The patient is a 61-year-old Caucasian man with longstanding diabetes mellitus type II, combined systolic and diastolic heart failure with an ejection fraction of 25%, atrial fibrillation with biventricular pacemaker, peripheral arterial disease status post right leg below the knee amputation several years ago, who was initially admitted to the hospital at the end of March 2019 for osteomyelitis of his left foot. He was placed on vancomycin, cefepime and metronidazole. He remained on these antibiotics until presenting to the hospital in mid-May from his skilled nursing facility (SNF) with hypotension, abdominal pain and profuse diarrhoea. The patient endorsed 3–4 days of worsening upset stomach and 2 days of increasingly frequent non-bloody diarrhoea. Admission findings included an elevated white cell count, an elevated lactate, acute kidney injury and severe hypotension. The patient was initially transferred to the medical intensive care unit but never required blood pressure support as his vitals improved with fluid resuscitation alone.

Investigations

To properly evaluate the patient’s diarrhoea and sepsis, a gastrointestinal stool pathogen panel, ova and parasites, and C. difficile assay were ordered. A CT scan of the patient’s abdomen and pelvis was also performed to evaluate for other intra-abdominal causes of the patient’s presentation. Blood cultures were also ordered. The leading item on the differential was fulminant CDI. Also considered were bacteraemia in the setting of known osteomyelitis and mesenteric ischaemia in the setting of severe abdominal pain and elevated lactate on presentation.

The patient’s C. difficile assay came back positive. His CT scan showed evidence of colitis. Reassuringly, both the CT scan and an abdominal X-ray did not show findings of ischaemia, toxic megacolon or ileus. His blood cultures and his stool pathogen panel were negative.

Treatment

Given the high concern for CDI, the patient was empirically placed on oral vancomycin and intravenous metronidazole before the assay came back positive. Despite early initiation of oral vancomycin and intravenous metronidazole and aggressive fluid resuscitation the patient remained seriously ill—with hypotension, an elevated white cell count and persistent watery diarrhoea with associated abdominal pain. The infectious disease service was consulted, and they confirmed that the patient met criteria for severe CDI. For the next week, the patient remained critically ill, with a white cell count of 27 000, significant anorexia and poor nutritional status, severe metabolic acidosis requiring sodium bicarbonate and persistent abdominal discomfort. After 9 days, the patient did not have improvement in his symptoms. He was transitioned to oral fidaxomicin with simethicone and dicyclomine for symptomatic relief. Although the dicyclomine somewhat relieved his abdominal pain and bloating, his discomfort and diarrhoea persisted. After 7 days on fidaxomicin, the patient still had no improvement in his symptoms and underwent his first FMT. Of note, during this procedure, the patient had an episode of severe hypotension and possible pulseless electrical activity in response to propofol used for anaesthesia, which quickly responded to a dose of epinephrine. After the first FMT, the patient had initial symptomatic relief for approximately 48 hours. However, he then began to experience persistent abdominal pain, bloating and up to 10 loose stools per day. He underwent a second FMT 1 week later, with a different anaesthesia dosing that the patient tolerated well. Again, the patient had 24–48 hours of symptom relief but then began to experience abdominal bloating and profuse watery loose stools. His postprocedure course was also complicated by severe anaemia, believed to be secondary to anaemia of chronic disease, requiring one blood transfusion. In mid-June, a third FMT was offered but the patient declined. He was placed back on a 10-day course of oral fidaxomicin and saw significant improvement in his symptoms after the first few days of antibiotics.

Outcome and follow-up

Although the patient’s abdominal pain and bloating never completely resolved, it improved significantly after being placed back on oral fidaxomicin. A third FMT was never required. The patient spent approximately 2 months in a SNF for acute rehabilitation. Despite vascular surgery recommendations, he declined amputation of his left foot. He recently required a brief rehospitalisation for further management of his chronic osteomyelitis, but has had no additional episodes of abdominal pain or diarrhoea. Notably, he has not yet been given additional antibiotics to further treat his osteomyelitis. If he does, he will likely be treated prophylactically with oral vancomycin to prevent recurrent CDI.

Discussion

The global disease burden of CDI has increased substantially over the past two decades, with increasing occurrence of refractory and recurrent CDI.^2–5 Current standard of treatment is based on disease severity and consists of vancomycin or fidaxomicin, though failure rates of these medications are increasing in incidence as well. FMTs are considered in recurrent or relapsing CDI given the treatment’s ability to diversify the gut microbiome.¹⁹ FMTs have been shown to cure up to 84% of refractory CDI with one procedure and up to 93.8% with repeated procedures. Patients can, however, be in the proportion of refractory CDI that does not respond to FMTs. In such cases, existing treatment algorithms are no longer beneficial.

In this case study, we described a 61-year-old Caucasian man with longstanding diabetes mellitus type II, combined systolic and diastolic heart failure, and a history of right below the knee amputation for osteomyelitis, who presented to our hospital with new osteomyelitis on two bones of his left foot. After antibiotic treatment targeting his osteomyelitis, he developed refractory CDI that failed treatment with vancomycin, metronidazole, fidaxomicin and two FMTs. After the second FMT, and in consultation with our gastroenterology and infectious disease colleagues, our team restarted the patient on another course of fidaxomicin. This antibiotic relieved his symptoms and resolved his difficult-to-treat CDI. Though little evidence exists, our case study suggests that FMTs can provide benefit without curing the CDI itself. We hypothesise that the FMTs changed our patient’s microbiome and created an environment more susceptible to standard therapy. If a provider encounters refractory CDI that fails standard treatment and multiple FMTs, we suggest reutilising standard therapy to target a more vulnerable microbiome and relieve the patient of difficult-to-treat CDI.

Patient’s perspective.

If telling my story can save one person, then I think that is well worth anything. I came into the hospital for an amputation of my left little toe up and treatment of an infection in my left foot. The antibiotics I was taking destroyed the natural bacteria that live in my stomach. I started on a downward spiral and was introduced to a word that I was not familiar: Clostridioides difficile.

It began a long course of trying to fight one thing without affecting the other. I endured mental stress but was not hopeless, because I knew my team was trying everything they could to make me better. After a month of treatment, we were losing options, so they tried a faecal matter transplant. They tried the first one, and it didn’t take. We tried it again, but nothing maintained a non-diarrhoeal state. Unfortunately, I was in the small percentage that failed these treatments.

It was difficult trying to maintain a positive attitude, but the team maintained a positive attitude which kept me fighting. After they tried the last antibiotic, it was a slow process, but I started to see the light at the end of the tunnel.

When I came in I weighed 185 pounds, and when I finally left I was 137 pounds. After I left the hospital, I went to a rehabilitation centre. They brought me back to 160 pounds and got me up on my feet so that I was able to walk. They brought me to a position where I could go home and spend time with my wife who has cancer. Now, I have hope.

Learning points.

• The global incidence of Clostridioides difficile infection (CDI) refractory to standard treatment is increasing, with growing resistance to antimicrobials worldwide.

• This is a unique case of severe, refractory CDI that did not respond to standard or novel treatments, including vancomycin, metronidazole, fidaxomicin and two faecal microbiota transplants (FMTs).

• In cases of refractory CDI, FMTs may diversify the colon’s microbiome to the extent that it is susceptible to reutilisation of standard treatments such as fidaxomicin.