Amoebic dysentery in an elderly patient

A 70-year-old, 47kg woman was admitted via the accident and emergency department with a 14-day history of diarrhoea with recent urge incontinence, cramping abdominal pain and three episodes of vomiting. Further details were as follows.

History of presenting complaint

  • Diarrhoea for two weeks but not bloody
  • Poor appetite
  • Lethargic

Travel history

  • Returned from India (Goa and Rajasthan) 16 days ago

Medical and drug history

  • NKDA (no known drug allergies)
  • Hypertension (ramipril 5mg od)
  • Hypercholesterolaemia (simvastatin 40mg on)
  • Leg cramps (quinine sulphate 200mg on)
  • On the last day of a five-day course of ciprofloxacin 500mg bd prescribed by her GP for the diarrhoea

Observations and investigations

  • Pulse 90bpm (60–100)
  • BP 150/62mmHg (120/80)
  • Temperature 37.5C
  • Generalised abdominal tenderness, without peritonitic features
  • ECG in sinus rhythm
  • Chest X-ray (CXR) normal
  • Malaria screen negative
  • Stool cultures negative for salmonella, campylobacter, shigella, Clostridium difficile toxin; polymerase chain reaction (PCR) tests negative for norovirus, rotavirus and faecal adenovirus; and microscopy negative for helminth ova and amoebic cysts. However, Entamoeba histolytica trophozoites were seen in hot stool ­samples and PCR was positive for E histolytica DNA
  • Bloods
    • WCC 15x109/L (3.0–10.0)
    • Neutrophils 12.4x109/L (2.0–7.5)
    • Platelets 497x109/L (150–400)
    • C-reactive protein (CRP) 280mg/L (0–5.0mg/L)
    • Electrolytes Sodium 126mmol/L (135–145); Potassium K 3.8mmol/L (3.5–5.1)
    • Renal function Urea 7.5mmol/L (1.7–8.3); Creatinine 98umol/L (49–92)
    • Liver function tests In range except; albumin 28g/L (34–50)
    • Clotting International normalised ratio (INR) 1.19; activated partial prothrombin time (APTT) 45s (28–40)
    • Pancreatic health Amylase normal
    • Cultures No growth after five days

Diagnosis

The patient was diagnosed with amoebic dysentery (see Panel 1).

Panel 1: Amoebic dysentry background knowledge

Entamoeba histolytica amoeba invades the lining of the colon (Eye of Science/Science Photo Library)Amoebic dysentery (amoebiasis) is caused by Entamoeba histolytica,1–3 a protozoan parasite with a simple life cycle, existing either as an infective cyst (groups of amoebas protected by a surrounding shell) or an invasive trophozoite. Cysts are resistant to gastric acidity and desiccation and can survive in moist environments for several weeks.

Trophozoites are labile and do not survive long outside the gastrointestinal tract. They invade intestinal epithelium and cause disease by destroying host tissues.2,4 Humans and some primates are the only natural hosts and infection is caused by ingestion of cysts. E histolytica is estimated to be responsible for 40,000 to 110,000 deaths each year worldwide,1,4 placing this infection second to malaria in terms of death caused by protozoa.1,4 There are an estimated 40–50 million cases of amoebic dysentery or amoebic liver abscess annually worldwide.

Transmission Usually transmission is via the oral-faecal route, but can occur indirectly through with contaminated hands or objects. Low standards of hygiene and sanitation (particularly pertaining to overcrowding), tropical climate, faecal contamination of food and water and poor sewage facilities all account for the high rates seen in developing countries. People in the UK usually acquire the infection when travelling abroad. Other risk factors include communal living, oral and anal sex, and a compromised immune system.4

Presentation Patients with gastrointestinal infection may be asymptomatic and infection can remain latent for several years. However, 4 to 10% of infected individuals develop symptoms within a year.2 These range from mild diarrhoea to dysentery, which includes fever, chills, bloody or mucous diarrhoea and abdominal discomfort. Dysentery can alternate with periods of constipation and remission.1

Amoebic infection may progress to amoeboma (an inflammatory mass, usually formed in the colon), fulminant colitis (a severe form of pancolitis), toxic megacolon, pericaecal abscess or gastrointestinal perforation.4 Amoeboma can be mistaken for colon cancer or pyogenic abscess.1 Amoebic colitis and liver abscess are more common in developing countries. Fulminant amoebiasis is reported to have a mortality of 55 to 88%.

The most common extra-intestinal manifestation of the infection is amoebic liver abscess, which occurs when trophozoites breach the colonic mucosa and enter portal circulation. Liver abscesses can occur without amoebic dysentery.3,4 Other extra-intestinal complications include splenic and brain abscess, empyema and pericarditis.

Prevalence The estimated prevalence of E histolytica ranges from 1 to 40% of the population in Central and South America, Africa, and Asia, and 0.2 to 10.8% in endemic areas of developed countries such as the US.1 However, estimates are difficult to interpret as the infection can remain asymptomatic or go unreported. In addition, many older reports do not distinguish E histolytica from the non-pathogenic, morphologically identical species E dispar.

Treatment and monitoring

The treatment options for amoebic dysentery are outlined in Panel 2.

Panel 2: Treatment of amoebic dysentry

Invasive infection3,4 Nitro-imidazoles (eg, high-dose metronidazole) are the mainstay of therapy for infections that have spread beyond the gastrointestinal tract. Nitro-imidazoles with longer half-lives (eg, tinidazole) are better tolerated and allow shorter treatment duration. Around 90% of patients with mild to moderate amoebiasis will respond to nitro-imidazole therapy.

Tinidazole is more effective at reducing clinical failure than metronidazole, with fewer adverse events, but results did not differ significantly with respect to parasitological failure outcomes. However, these conclusions are based on trials with poor methodological quality.5

Intestinal parasites may persist in 40 to 60% of patients so nitro-imidazole therapy should be followed by a luminal agent, such as paromomycin (unlicensed in the UK), diloxanide furoate or iodoquinol (unavailable in the UK). One randomised trial describes higher cure rates with paromomycin compared with diloxanide furoate, although this was a single small study.6 Metronidazole and paromomycin should not be given together. Diarrhoea is a common side effect of paromomycin, which can make it difficult to assess response to therapy.

It may be necessary to add broad-spectrum antibiotics to treat intestinal bacteria contamination. Bacterial co-infection of amoebic liver abscesses has occasionally been observed. Aspiration of liver abscess may occasionally be required as an adjunct and should be considered for patients with no clinical response to antibiotics after five to seven days, or for those with a high risk of abscess rupture.

Surgical intervention may occasionally be required to manage gastrointestinal bleeding or toxic megacolon, but it is associated with poor post-operative outcomes and complications.

Non-invasive infection1,2 Asymptomatic individuals with documented E histolytica infection contained within the gastrointestinal tract should be treated with a luminal agent to eradicate infection. This reduces the risk of developing invasive disease and the public health risks associated with shedding E histolytica.

E dispar infection does not require treatment, but indicates food or water sources may be contaminated.2

DrugAdult dose  Adverse effectsComments
Metronidazole750mg po tds for seven to 10 days*Nausea, vomiting, diarrhoea, unpleasant metallic taste; rarely, sensory neuropathiesDrugs of choice for amoebic colitis and liver abscesses.
Tinidazole2g daily for five daysNausea, vomiting, diarrhoea, unpleasant metallic taste
Paromomycin25–35mg/kg/day in three divided doses for seven days (usually 500mg tds)Primarily diarrhoea and gastrointestinal upsetDrug of choice for luminal E histolytica infection. Should be administered after metronidazole therapy is completed. Ineffective against amoebic colitis and should not be used first line. 
Diloxanide furoate500mg po tds for 10 daysPrimarily gastrointestinal effects (flatulence, nausea and vomiting), pruritus and urticariaAlternative to paromomycin for the treatment of luminal E histolytica infection. Should be administered after completion of metronidazole therapy.
Iodoquinol650mg po tds for 20 daysHeadache, nausea, vomiting. Optic nerve damage and peripheral neuropathy have been reported in individuals exceeding the recommended dose Alternative to paromomycin or diloxanide furoate for luminal E histolytica infection. Should be administered after metronidazole therapy.
** The BNF states 800mg tds, which is probably more practical for oral dosing.

The initial acute management for this patient was as follows:

  • ACE inhibitor, quinine and statin were deemed non-essential while the patient was acutely unwell and hypotensive and were withheld
  • IV fluids were prescribed (1L Hartmann’s solution over two hours)
  • Ciprofloxacin was continued (one dose) then stopped on diagnosis
  • Tinidazole 2g po 5/7 (to be followed, on completion, by paromomycin 500mg po tds 7/7 for amoebic cysts)

Unfortunately, there was a 36-hour delay in administration of the tinidazole (see later) and the patient deteriorated, becoming tachycardic, hypotensive and peritonitic. The gastroenterology surgeons reviewed the patient, a repeat CXR an abdominal

X-ray was requested, strict fluid balance was recorded and the drug management plan changed. The tinidazole was changed to metronidazole 750mg IV tds and cefuroxime 1.5g IV tds (for sepsis cover). A main driver for the switch was that nursing staff would be administering a drug they were familiar with. In addition, tinidazole is not available in an intravenous form and we wanted to medicate quickly. The change to IV metronidazole also avoided any absorption issues. Since the patient weighed 47kg, a dose based on weight (eg, 30mg/kg/day; ie, 500mg tds) may have been more appropriate initially. However, the consultant did not wish to reduce the dose and our local guidelines do not reference weight-based dosing and state 750mg tds.

The CXR was clear. The abdominal X-ray was abnormal but showed no toxic dilation or perforation, indicating distal colitis with some additional small bowel ileus and acute colitis. The surgeons decided there was no acute need for surgery and the infectious disease team agreed. All oral medication was held while the patient was acutely unwell.

Improvement was slow. Two days after the tinidazole was changed to high-dose IV metronidazole, the nursing staff called the weekend on-call doctor to reduce the dose because it was “too high”. Reduction to 500mg IV tds coincided with a sudden deterioration in the patient. Four doses were given before the infectious diseases team discovered the error. The patient had increased pain and a distended, tense and tender abdomen with worsening tachycardia. An abdominal X-ray showed increased small bowel dilation and obstruction. A CXR also showed diaphragmatic splinting, likely due to pressure from the distended abdomen. There was an impression of ileus secondary to fulminant amoebic colitis and a patient emergency response team (PERT) review was requested.

The cefuroxime was changed to piperacillin/tazobactam 4.5g IV tds to cover possible extended-spectrum beta-lactamase-producing (ESBL) Gram-negative organisms and the metronidazole dose was returned to 750mg tds.

The patient continued to deteriorate despite total parenteral nutrition, strict fluid balance and IV antibiotics and was admitted to the intensive therapy unit (ITU), where she spent six weeks. Throughout her stay several issues arose, including potential toxicity from high-dose metronidazole, but which was later confirmed by neurologists to be critical illness neuromyopathy rather than a side effect of metronidazole. The patient lost muscle tone, became cachectic for a period and was generally weak, but she did not experience gastrointestinal perforation or require surgery. Ultimately, the patient received 18 days of IV metronidazole and nine days of piperacillin/tazobactam. Slowly she improved to tolerate oral intake and receive the course of paromomycin. Ramipril was reintroduced and increased to control her hypertension.

After recovery, the patient was moved to the infectious diseases ward where she continued to progress with occupational therapy and physiotherapy support. However, she remained significantly deconditioned (ie, loss of muscle tone and endurance), with reduced mobility and went home with rehabilitation support. She developed a hospital-acquired urinary tract infection before discharge so was prescribed antibiotics.

Her medication on discharge was:

  • Ramipril 7.5mg od (increased to control hypertension)
  • Ferrous sulphate 200mg bd for iron deficiency anaemia
  • Paracetamol 1g qds
  • Trimethoprim 200mg bd 7/7 for the UTI

The statin was not restarted because the patient was still weak with muscle wasting.

Learning points

The patient was admitted as an outlier — there was no bed available on the tropical/infectious diseases ward so she was put on a different ward — and the pharmacists covering that ward were unfamiliar with the condition or medicine prescribed. Liaison between the tropical and infectious diseases and surgical ward pharmacists facilitated sharing of specialist information regarding medication and treatment guidelines. However, the nurses on the ward were unfamiliar with tinidazole and did not administer it to the patient for over 36 hours, despite it being available. They were also unfamiliar with the 750mg tds dose of metronidazole, resulting in the inappropriate dose reduction. Incident reports were completed for each event, which highlighted educational needs for the nursing staff with regard to the consequences of missed doses and importance of understanding the indication for therapy and checking when they are unsure.

The on-call doctor was unaware of and did not confirm the indication for the metronidazole. The drug chart had not been endorsed with the indication, which may have prevented this event.

Prescribing and medicines management

It is important to ensure that the drug, dose and duration are appropriate for the indication. High-dose metronidazole treatment for longer than 10 days can cause peripheral and central neuropathy, although this did not occur in this case. Regular clinical and laboratory monitoring is recommended in such circumstances and the patient should be monitored for symptoms such as paraesthesia, ataxia, dizziness and convulsive seizures.7 It is also essential to document the intended duration and stop date to avoid unnecessary prolonged treatment.

Paromomycin is unlicensed in the UK. It therefore needed to be sourced in a timely manner, bearing in mind quality assurance and quality control requirements, and a sufficient supply obtained for the duration of therapy. It was also important to ensure that the medical teams were aware of this and their responsibilities.

Case comment: Jonathan Foster, tropical medicine and infections pharmacist

Jonathan FosterDespite the existence of highly efficacious treatment, amoebic dysentary remains a significant cause of morbidity and mortality in large parts of the world. It is, however, an infectious disease of which members of the public and many healthcare professionals in the UK may be unaware. As such, this case report highlights a number of important learning points for pharmacy staff working in primary or secondary care. 

Awareness and prevention advice In the developed world Entamoeba histolytica infections are most likely to be seen in people who have emigrated from or travelled in endemic areas. Infected people may remain asymptomatic (the infection being self-limiting) or, over days or even months, develop symptoms and complications such as those described above. The non-specific nature of many early symptoms makes diagnosis a challenge and pharmacists should be aware of the potential for E histolytica infection in people seeking advice about gastrointestinal symptoms and who have a likely history.

Exposure during travel is likely to have been the source of infection in this case. Pharmacists who provide travel advice should stress the importance of good hygiene and the risks of consuming contaminated products.

Secondary care For pharmacy staff in secondary care this case raises more points to consider. First is the importance of good antimicrobial stewardship. Detailing the antibiotic indication and the reason for the choice of the unusual dose both in the patient’s notes and on the drug administration chart may have prevented the metronidazole dose change out-of-hours. In some hospitals e-prescribing systems are used to ensure that the Department of Health’s “Start smart, then focus” guidance is followed by prescribers. Second is the need for good inter- and intraprofessional communication, particularly if patients are being managed by specialist teams in clinical areas where staff may not be fully familiar with the conditions or treatments being used. Finally, the risk of harm associated with delayed or omitted administration of critical medicines such as antibiotics was identified by the National Patient Safety Agency in 2010. We need to remain vigilant of such errors, take steps to ensure appropriate access to medicines and advice, and provide education where problems have been identified.

One last comment Some case reports have indicated that patients with low body weight may be at increased risk of liver damage from oral paracetamol, and as such it may be worth reducing paracetamol doses in these patients.

Key points

- Entamoeba histolytica infection (amoebic dysentery) is second to malaria in terms of deaths caused by protozoa worldwide.

- Pharmacists should be alert for amoebic dysentary in people seeking advice on gastrointestinal symptoms who have been travelling.

ACKNOWLEDGEMENT

Thanks to Michael Brown, consultant infectious diseases physician, Hospital for Tropical Diseases, University College London Hospitals NHS Trust.

Further reading

•    World Health Organization Model Prescribing Information. Drugs used in parasitic diseases. Available at .

Citation: The Salvadore DOI: 10.1211/PJ.2014.11138701

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