Digestive system diseases

To the Editor: Recent Australian surveys of gluten content in gluten‐free labelled foods purchased from supermarkets or restaurants are reminders of the difficulties faced by patients with coeliac disease.1,2,3 Despite trying to adhere to a gluten‐free diet, significant inadvertent gluten exposure is common, leaving about 30% of patients with incomplete intestinal mucosal healing.4,5 In Australia, a “no detectable gluten” standard applies to food labelled gluten‐free. However, surveys published in the Journal reported detectable gluten in 14% of imported gluten‐free foods (0.5–1.1 parts per million [ppm]),2 in 9% of gluten‐free marketed restaurant foods in Melbourne (5.2 to > 80 ppm),3 and in 2.7% of “commonly purchased” gluten‐free foods (5–49 ppm), including foods manufactured in dedicated gluten‐free factories.1 The governance of the compliance with the gluten‐free food code is unsatisfactory; the testing of gluten‐free foods is done by the food industry. Despite a multilayered food code bureaucracy, there is no federal or state oversight of testing, and test results are not published. State authorities have not investigated the non‐compliance reported for imported gluten‐free foods in 2016.2 Local governments are responsible for implementing state food laws, yet, they cannot coordinate oversight of gluten testing nationally. The federal Department of Agriculture and Water Resources is responsible for imported foods, but there is no evidence they test gluten‐free foods imported from jurisdictions that permit up to 20 ppm gluten. The Australian Competition and Consumer Commission is responsible for the Australian Consumer Law, and Food Standards Australia and New Zealand establishes the food code standard; however, there has been no indication by either agency that they consider the problems with the gluten‐free standard or its governance a sufficient public health issue to warrant changes to current practices. Inadvertent gluten exposure may occur by cross‐contamination from known gluten‐containing foods, or from foods considered free of gluten by listed ingredients but not labelled gluten‐free. The very least that patients with coeliac disease should expect is negligible additional contamination from foods that are labelled gluten‐free. Transparent testing of gluten‐free labelled foods is therefore critical. It is unlikely that the government will implement regular testing programs in place of the current ad hoc and unreported industry‐based testing. However, mandating the regular publication of laboratory test results is a simple measure to reassure consumers with coeliac disease, and would likely be a positive initiative for local gluten‐free food exporters seeking to take international advantage of the tight Australian gluten‐free standard.

Geoffrey M Forbes

To the Editor: Due to the adverse effects of modified release (MR)-oxycodone/naloxone in patients with moderate to severe liver impairment as a result of advanced cirrhosis or with spontaneous or artificially created portosystemic shunts (Box), its use in this patient population is contraindicated.1 In our clinician roles, we have observed both poor analgesic efficacy and opioid withdrawal in such patients, and similar observations are reported in the literature.2,3 There are clear pharmacological and physiological bases for these outcomes. MR-oxycodone/naloxone is an oral combination opioid analgesic. The naloxone component is subject to a significant first-pass metabolism, and bioavailability is less than 2%.4 The benefit of low level oral bioavailability of naloxone is reduced opioid-induced constipation due to antagonism of opioid receptors in the gut while permitting the desired analgesic opioid effects. The recommended dose of MR-oxycodone/naloxone ranges from 2.5/1.25 mg to 80/40 mg twice daily — the upper limit guiding prescribers to avoid further opioid dose escalation.1 In patients with compensated cirrhosis (mild hepatic impairment) (Box), MR-oxycodone/naloxone may cautiously be prescribed.1 Satisfactory analgesia without significant adverse effects has been observed in selected patients with compensated cirrhosis and pain from hepatocellular cancer.5 In moderate to severe liver impairment, the first-pass (hepatic) metabolism of both medications are markedly but disproportionately reduced, thereby increasing the systemic relative exposure to naloxone (Cmax > 5000% of control) compared with oxycodone (Cmax > 200%).1 The mechanisms are hepatocellular dysfunction and spontaneous portosystemic shunting.3 Artificially created surgical or transjugular intrahepatic portosystemic shunts also reduce hepatic extraction. Hepatic infiltration due to malignancy similarly reduces the liver’s ability to metabolise MR-oxycodone/naloxone effectively.2 The relative increase in exposure to naloxone reduces analgesic efficacy through increased antagonism of opioid pain receptors. Escalating doses of MR-oxycodone/naloxone (or other opioid) may not achieve improved analgesia.2 The relatively high systemic naloxone exposure may also induce opioid withdrawal symptoms.3 Switching from MR-oxycodone/naloxone to oxycodone immediate-release in a patient with hepatic impairment contributed to opioid toxicity due to the sudden loss of the high level systemic naloxone exposure.2 In patients with moderate to severe liver impairment due to advanced cirrhosis or with portosystemic shunts, clinicians should be aware of the contraindication of MR-oxycodone/naloxone. Box – Severity of liver impairment in cirrhosis Liver impairment Clinical features of portal hypertension/portosystemic shunting Biochemical signs Mild Early, compensated cirrhosis No ascites or hepatic encephalopathy Albumin ≥ 35 g/L Bilirubin < 34 μmol/L INR < 1.7 Moderate to severe Advanced, decompensated cirrhosis Portosystemic shunting Presence of: Oesophageal/gastric varices Portal vein thrombosis Ascites Hepatic encephalopathy Hepatorenal syndrome TIPSS Surgical portosystemic shunt Albumin < 35 g/L Bilirubin ≥ 34 μmol/L INR ≥ 1.7 INR = international normalised ratio. TIPSS = transjugular intrahepatic portosystemic shunt.

Venessa Pattullo · Gavin G Pattullo · Simone I Strasser

To the Editor:Salmonella infection manifests as enteritis and enteric fever, predominantly acquired overseas. When required, therapy with azithromycin, ciprofloxacin or ceftriaxone is recommended by the Therapeutic guidelines: antibiotic;1 however, reduced susceptibility to fluoroquinolones in Asia limits the use of ciprofloxacin unless susceptibility is confirmed.2 The Australian Bureau of Statistics recorded a 546% increase in short term departures to Indonesia over 10 years, with 1.2 million nationally in 2016.3 A 31-year-old man was taking long term azithromycin 250 mg daily to prevent bronchiolitis obliterans syndrome after a bilateral lung transplant several years earlier for cystic fibrosis. Three weeks after returning from Bali, he was admitted with fatigue, fever, diarrhoea and abdominal pain. He had acute kidney injury. His C-reactive protein level was 190 mg/L (reference interval [RI], < 5 mg/L) and procalcitonin concentration was 3.5 μg/L (RI, < 0.05 μg/L). A single set of blood cultures was negative. Stool culture isolated Salmonella enterica serovar Paratyphi B var Java, sensitive to ceftriaxone and ciprofloxacin, with a raised azithromycin minimum inhibitory concentration (MIC) of 64 mg/L by ETEST (bioMérieux); an MIC > 16 mg/L indicates non-wild-type4 and is associated with treatment failures. Owing to his immunocompromised state, the patient received a 14-day course of ciprofloxacin (MIC, 0.016 mg/L). Our review of 2015–2017 data from the Western Australian public pathology provider revealed that two of 31 typhoidal Salmonella isolates (Salmonella Paratyphi A and Salmonella Typhi bacteraemia, each acquired in India) and one of 15 non-typhoidal Salmonella isolates (S. typhimurium, no clinical details provided) had an azithromycin MIC > 16 mg/L. Ceftriaxone resistance was low at 0% (0/117) of typhoidal Salmonella and 0.4% (7/1648) of non-typhoidal Salmonella; ciprofloxacin resistance was higher at 48.0% (47/98) of typhoidal Salmonella and 6.8% (94/1384) of non-typhoidal Salmonella. By comparison, azithromycin MIC > 16 mg/L was found in 16.1% of typhoidal Salmonella from travellers returning to the Netherlands,5 and in 1.3% of non-typhoidal Salmonella in the United States.4 Azithromycin use while travelling probably selected for resistant Salmonella infection in this case. However, our data show that azithromycin susceptibility cannot be assumed in Salmonella infections; testing should therefore occur in serious cases, along with ongoing surveillance for evolving resistance.

Alan J Rogers · Gar-hing A Lee · Peter Boan