Antimicrobial Stewardship and Resistance — Viva

Long Case Viva Defence

Candidate's opening statement (model answer)

"Mrs Eleanor Whitcombe is a 72-year-old retired schoolteacher who was admitted 7 days ago with healthcare-associated pneumonia and treated with intravenous ceftriaxone 2 g daily, and who now presents with severe and fulminant Clostridioides difficile infection complicating that course — profuse watery diarrhoea, fever, hypotension, a white cell count of 26 and a creatinine doubled from her baseline, with a stool toxin assay positive and the isolate ribotyped as NAP1/BI/027, the hypervirulent strain. She has had one previous episode of C. difficile infection 8 months ago, treated with oral vancomycin. ^[1]

Her main problems are:

1. Fulminant C. difficile infection with circulatory compromise and acute kidney injury, on a background of the NAP1/027 strain.
2. The resolved healthcare-associated pneumonia (the inciting course of ceftriaxone).
3. A high risk of recurrence — age above 65, severe index episode, prior CDI within the year, NAP1/027 strain.
4. Acute kidney injury from dehydration and the inflammatory colitis.
5. Age-related frailty and the inpatient complications of a prolonged admission. ^[1]

Her management has been to stop the inciting ceftriaxone, start oral vancomycin 500 mg four times daily plus intravenous metronidazole 500 mg every 8 hours, administer a single dose of bezlotoxumab 10 mg/kg intravenously for recurrence prevention, resuscitate with intravenous crystalloid, place her in a single room with contact precautions and soap-and-water hand hygiene, and request an urgent surgical review for the fulminant picture. Her plan is to complete a 14-day course with transition to fidaxomicin or a vancomycin taper once she is stable, to arrange faecal microbiota transplantation if she recurs again, and to conduct a stewardship review of the inciting antibiotic to prevent a further episode." ^[1]

Examiner probing questions and model answers

Q1: "Walk me through why you chose oral vancomycin 500 mg four times daily plus IV metronidazole for this episode, rather than fidaxomicin, and why not metronidazole alone as we used to use." ^[1]

"The decision is driven by severity. The 2018 IDSA/SHEA guideline stratifies CDI into initial non-severe (white cell count below 15 and creatinine below 1.5 times baseline), initial severe (white cell count 15 or above or creatinine 1.5 times baseline or above), and fulminant (hypotension, shock, ileus, toxic megacolon) ^[2]. Mrs Whitcombe has a white cell count of 26 and a creatinine more than doubled, placing her in severe disease, and she is hypotensive with a heart rate of 112 and clinical dehydration, placing her in fulminant disease. The recommended regimen for fulminant CDI is oral vancomycin 500 mg four times daily PLUS intravenous metronidazole 500 mg every 8 hours — the higher vancomycin dose achieves high intraluminal colonic concentrations in the face of an oedematous, inflamed mucosa and reduced gut motility, and the IV metronidazole provides systemic cover because oral vancomycin is not absorbed and may not reach the colon in adequate concentration if ileus develops. I would add a vancomycin rectal retention enema (500 mg in 100 mL normal saline every 6 hours) if she develops an ileus.

Fidaxomicin is first-line for non-severe and severe (non-fulminant) CDI, where its recurrence advantage over vancomycin (15 versus 25 per cent in the Louie trial) ^[5] is the principal benefit. In fulminant disease with shock, the evidence for fidaxomicin is weaker, and the standard remains high-dose vancomycin plus IV metronidazole. Once she stabilises and is absorbing orally, I would transition to fidaxomicin to complete the course and to gain the recurrence benefit.

Metronidazole alone is no longer recommended for any adult CDI — the 2018 guideline replaced it with fidaxomicin and oral vancomycin because of higher recurrence and lower cure in severe disease, and because of the neurotoxicity and the systemic side effects of prolonged oral metronidazole. Metronidazole retains a role only as an IV adjunct in fulminant disease and as a third-line oral option where the preferred agents are unavailable." ^[1]

Q2: "She is ribotyped as NAP1/BI/027. What does this mean clinically, and does it change your management?" ^[1]

"The NAP1/BI/027 strain is the hypervirulent strain first described by Loo and colleagues in the Quebec outbreak of 2002 to 2005, where it was associated with markedly higher morbidity and mortality than historical strains — attributable mortality of 6.9 per cent at 30 days and 16.7 per cent at one year in patients aged 60 and above ^[6]. The strain carries three features that drive its hypervirulence: a deletion in the tcdC gene (a negative regulator of toxin A and B production, leading to 16- to 23-fold higher toxin levels), production of binary toxin (whose role is still being characterised), and fluoroquinolone resistance (which gave it a selective advantage during the fluoroquinolone era and allowed its rapid spread). Clinically, NAP1/027 is associated with severe and fulminant presentations, a higher risk of toxic megacolon and colectomy, higher recurrence, and higher mortality — particularly in older patients.

The acute management does NOT change with the ribotype — the severity-based regimen I described applies regardless of strain. But the ribotype does four things. First, it raises my threshold of concern for deterioration and for surgical review — NAP1/027 progresses to toxic megacolon faster. Second, it strengthens the case for bezlotoxumab and for fidaxomicin over vancomycin in the recurrence-prevention phase, because NAP1/027 has higher recurrence. Third, it is a notifiable finding that the infection-control team and public health want to know about, because it indicates the strain is present in the facility and may be spreading. Fourth, it is an argument for the stewardship review — fluoroquinolone and cephalosporin exposure select for NAP1/027, and the ceftriaxone course that precipitated her CDI is part of the chain that allows this strain to predominate." ^[1]

Q3: "She has had one prior episode. Tell me about bezlotoxumab and about faecal microbiota transplantation — when, why, and how." ^[1]

"Bezlotoxumab is a fully human monoclonal antibody against Clostridioides difficile toxin B, designed to supplement the antibiotic effect by binding and neutralising toxin B in the gut for up to 12 weeks after a single intravenous infusion. The MODIFY I and MODIFY II randomised trials demonstrated that bezlotoxumab 10 mg/kg intravenously, given WITH standard antibiotic therapy, reduced the 12-week recurrence rate from 26.6 per cent in the placebo group to 16.5 per cent in the bezlotoxumab group ^[3]. The benefit was greatest in the patients at highest recurrence risk — age 65 and above, immunocompromised, severe index episode, and one or more prior episodes in the past 6 months — which is exactly Mrs Whitcombe. She therefore meets the indication on every criterion. The main adverse effect is heart failure exacerbation in patients with pre-existing heart failure (a 12.7 versus 4.8 per cent rate of heart failure death or hospitalisation in the trial, prompting an FDA warning), so I would check she has no heart failure history before administering it. She has a single dose on day 1 of therapy.

Faecal microbiota transplantation (FMT) is the most effective treatment for multiply-recurrent CDI. The mechanism is restoration of the colonic microbiome and its resistance to C. difficile colonisation. The pivotal van Nood randomised trial in 2013 compared duodenal infusion of donor faeces with vancomycin (with or without bowel lavage) in patients with recurrent CDI; it was stopped early for efficacy because 81 per cent of the FMT group achieved cure after a single infusion (94 per cent after a second infusion), versus 31 per cent on vancomycin alone ^[4]. FMT is delivered by nasoduodenal tube, colonoscope, or capsule; the donor is rigorously screened for enteric pathogens, multi-resistant organisms, and now SARS-CoV-2. The indication is a second or subsequent recurrence — not the initial episode, and not the first recurrence. For Mrs Whitcombe's CURRENT episode, FMT is not yet indicated; if she recurs again after this episode, FMT would be the next step."

Q4: "What are the stewardship lessons from this case — what went wrong, and how would you prevent it at the programme level?" ^[1]

"The stewardship lessons are several. First, the inciting antibiotic matters. Ceftriaxone is a third-generation cephalosporin, one of the highest-risk antibiotic classes for C. difficile infection because of its profound disruption of anaerobic gut flora and its biliary excretion producing high intestinal levels. The question for her healthcare-associated pneumonia is whether ceftriaxone was the right drug, the right dose, and the right duration — and whether it could have been narrowed, shortened, or avoided. A stewardship audit of her case would review the indication, the duration against the evidence (most healthcare-associated pneumonia resolves within 7 days, and her 7-day course was at the upper end), and whether she met criteria for IV-to-oral switch earlier. ^[1]

Second, the duration of therapy is the most modifiable risk factor for CDI. The 2016 IDSA/SHEA stewardship guideline identifies the antibiotic timeout at 48 to 72 hours — a mandatory review of the continuing indication, the spectrum, the dose and the duration — as one of the two core interventions ^[1]. If her ceftriaxone had been reviewed at 48 hours and narrowed or stopped when her pneumonia improved, the CDI may have been prevented.

Third, the prevention of recurrence is itself a stewardship activity — every further antibiotic course in this patient predisposes to recurrence, so minimising unnecessary antibiotics for the rest of her life is preventive. ^[1]

At the programme level, the interventions are: pre-authorisation restricting broad-spectrum cephalosporins and carbapenems to infectious diseases approval; prospective audit and feedback reviewing every patient on broad-spectrum therapy at 48 to 72 hours; facility-specific treatment guidelines for common infections (community- and healthcare-associated pneumonia, urinary tract infection, intra-abdominal infection, sepsis) that favour narrow-spectrum first-line therapy and short durations; IV-to-oral switch protocols; dose optimisation with therapeutic drug monitoring; and a C. difficile surveillance programme that reports rates by ward and triggers outbreak investigation. The single most effective intervention is the 48-hour review with mandated de-escalation — most unnecessary antibiotic days are after day 2, when the patient is improving and cultures have returned but the broad-spectrum regimen is continued reflexively." ^[1]

Q5: "How would you counsel her and her family about what has happened and the road ahead?" ^[1]

"I would sit down with her and her family, with an interpreter if there is any language barrier, and explain clearly. I would tell them that the antibiotic she received for her pneumonia, while necessary at the time, disrupted the normal bacteria in her bowel and allowed a germ called C. difficile to overgrow and release a toxin that caused the diarrhoea and inflammation. I would explain that this germ is sometimes more aggressive than others — this particular strain, the NAP1/027, is known to cause more severe illness — and that we are treating it with two antibiotics: vancomycin by mouth that targets the germ directly in the bowel, and metronidazole through the drip that works throughout the body. I would explain that we are also giving her a single infusion of an antibody called bezlotoxumab that mops up the toxin and reduces the chance of the infection coming back. I would be honest that this is a serious illness in an older patient, that she will need close monitoring, and that if she does not respond there is a surgical option (removing the colon) that can be life-saving. ^[1]

For the road ahead, I would explain the concept of recurrence — that the infection comes back in about a quarter of patients, more often after multiple episodes — and that the most important thing we can do to prevent it is to minimise her exposure to antibiotics in the future. I would give her written information about C. difficile, an alert card, and clear instructions to seek early review if diarrhoea recurs. I would communicate the plan to her general practitioner, document the CDI and the inciting antibiotic in her record, and arrange a follow-up with the infectious diseases and gastroenterology teams. The communication is part of the treatment — a patient who understands the illness and the plan recognises recurrence early and seeks help." ^[1]