Pharmacology

To the Editor: Pharyngitis, a common childhood illness, accounts for around 3% of presentations to general practice in Australia.1 Although usually benign and self‐limiting, group A streptococcus (GAS) pharyngitis, isolated in up to 20% of symptomatic children,2 can lead to infectious and autoimmune sequelae. Despite Australia being a high income country, acute rheumatic fever (ARF) and rheumatic heart disease (RHD) still cause significant morbidity and mortality in Aboriginal and Torres Strait Islander people.3 Prompt treatment of GAS pharyngitis has been shown to reduce the incidence of ARF by two‐thirds in high risk individuals.4 Low risk individuals require supportive management only.5 Clinical diagnosis of GAS pharyngitis is unreliable4 and culture results take time. As such, clinicians must balance the competing priorities of appropriate treatment of patients at high risk of ARF or RHD with prudent antimicrobial stewardship. Clinical practice guidelines play an important role in decision making at both a population and individual level. We undertook a search to identify Australian and New Zealand pharyngitis guidelines and compared these with previously published criteria.6 Nine guidelines were identified. Inconsistences in diagnosis, definition of high risk groups, analgesia, antibiotic rationale, agent, therapy duration, and tonsillectomy indications were observed (Box). Australia's multitude of heterogenic guidelines coupled with the transient workforce in remote Australia, where ARF burden is the highest,7 predispose to management confusion and potential poor patient outcomes, including higher rates of ARF and RHD, and also fail to address the growing worldwide problem of antimicrobial resistance. Australia needs a single national pharyngitis guideline to assist in providing rational, consistent and timely antibiotic treatment to patients at high risk of ARF, while minimising inappropriate antibiotic usage and resistance in individuals at low risk of sequelae. We call for an evidence‐based guideline that includes the following: a clear, succinct approach to diagnosis and management; a definition of individuals at high risk of ARF, and rationale for antibiotic treatment; clear guidance regarding throat culture and point‐of‐care testing for GAS; rationale for first‐ and second‐line empirical antibiotics, with alternatives for penicillin allergy; capacity to adapt management in different clinical settings; and supportive care recommendation including analgesia, tonsillectomy and school exclusion. Box – Summary of selected criteria:6 are criteria addressed by each sore throat guideline? Guidelines NZ HF BPAC NZ CH QLD NSW ICCPG CARPA RHD Aust PCH RCH eTG Number of criteria addressed 6/12 7/12 2/12 10/12 7/12 6/12 10/12 9/12 10/12 Diagnostic criteria × × × ✓ ✓ × ✓ × ✓ Routine throat culture/rapid antigen detection testing ✓ ✓ × ✓ × ✓ ✓ ✓ × Antibiotics to reduce symptoms × ✓ × ✓ × × ✓ × ✓ Antibiotics to prevent complications ✓ ✓ × ✓ ✓ ✓ ✓ ✓ ✓ NZHF = New Zealand Heart Foundation (http://www.heartfoundation.org.nz/shop/heart-healthcare/non-stock-resources/sore-throat-algorithm.pdf); BPAC = Best Practice Advocacy Centre (https://bpac.org.nz/antibiotics/guide.aspx#sore-throat); CH QLD = Children's Health Queensland Hospital and Health Service guidelines (http://www.childrens.health.qld.gov.au/chq/health-professionals/antimicrobial-stewardship/guidelines/ent-infections); NSW ICCPG = New South Wales infants and children clinical practice guidelines (http://www1.health.nsw.gov.au/pds/ActivePDSDocuments/GL2014_021.pdf); CARPA = Central Australian Rural Practitioners Association's standard treatment manual (https://docs.remotephcmanuals.com.au/review/g/manuals2017-manuals/d/20321.html?page=115); RHD Aust = rheumatic heart disease Australian guidelines (https://www.rhdaustralia.org.au/arf-rhd-guideline); PCH = Perth Children's Hospital emergency department guidelines (https://pch.health.wa.gov.au/For-health-professionals/Emergency-Department-Guidelines/Tonsillitis); RCH = Royal Children's Hospital Melbourne guidelines (with support of the Victorian Paediatric Clinical Network) (www.rch.org.au/clinicalguide/guideline_index/Sore_throat); eTG = electronic therapeutic guidelines (https://tgldcdp.tg.org.au/searchAction?appendedInputButtons=sore%20throat). ◆

Adrian J Tarca · Robert M Hand · Rosemary Wyber

To the Editor: Patients may require long term anticoagulation for reasons that commonly include deep vein thrombosis, pulmonary embolism or atrial fibrillation.1 In these circumstances, heparin is commonly used for bridging and is discontinued after the effects of warfarin result in a therapeutic international normalisation ratio. It takes approximately 5 days for this to occur because warfarin inhibits the production of vitamin K‐dependent clotting factors II, VII, IX and X.2 The time to therapeutic anticoagulation is a reflection of the half‐lives of the circulating clotting factors and the time for them to diminish from the plasma. This has been our mindset for decades from the perspective of warfarin use. The introduction of direct‐acting oral anticoagulants (DOACs), such as apixaban, dabigatran and rivaroxaban, has resulted in important logistical and clinical benefits in patients admitted to hospital. For example, bridging with heparin is no longer needed3 because DOACs directly inhibit circulating clotting factors resulting in a relatively quick onset of anticoagulation. The maximum concentration in the plasma is achieved within a few hours, which also mirrors its anticoagulant effect.4 Unfortunately, based on internal audits at our institution, our medication safety committee has identified cases in which DOACs were combined with heparin or low molecular weight heparin. During a 38‐day audit period, there were 14 cases involving such duplication. Based on anecdotal discussions, this duplication is partly related to the prescribers’ lack of knowledge with regards to DOACs. Nurses or pharmacists usually intercepted these events such that the overlap occurred for a few doses and no patients were harmed. In the shift from warfarin to DOACs, inadvertent and unnecessary duplicate anticoagulation due to bridging increases the risk of bleeding. Although we seldom use absolutes, we can confidently endorse that there are no circumstances in which DOACs should be combined with another anticoagulant. Prescriber education and clear institutional guidelines may help deal with this issue. In addition, institutions with electronic medical records could optimise clinical decision support systems to prevent such duplication. The combination of DOACs with heparin is a bridge to nowhere.

Mark A Sheppard · Russell Levy · Asad E Patanwala

TO THE EDITOR: In 2016, there were an estimated 490 000 cases globally of multidrug‐resistant (MDR) tuberculosis exhibiting resistance to isoniazid and rifampicin.1 The first case of MDR tuberculosis diagnosed in Tasmania occurred in 2016 in a Vietnamese‐born person. Vietnam was the second highest reported country of birth for overseas‐born patients with tuberculosis notified in Australia in 2014.2 The patient had previously tested positive for tuberculosis infection in an interferon‐γ release assay test performed in Tasmania in early 2016, but at the time, the patient was asymptomatic and had a normal chest x‐ray and a negative sputum culture. After an episode of colitis, a colon tissue biopsy specimen isolated Mycobacterium tuberculosis. Whole genome sequence of the isolate (TASMDR1), identified high confidence mutations for isoniazid, rifampicin, ethambutol and pyrazinamide, in accordance with the culture‐based drug susceptibility testing, and, in addition, it identified a mutation associated with streptomycin resistance.3 We became aware that a household contact of the Tasmania‐located patient with MDR tuberculosis had been diagnosed with pulmonary tuberculosis in Vietnam in 2012 and requested the drug susceptibility testing data for this isolate (VTB1) from the treating hospital in Ho Chi Minh City. VTB1 was resistant to isoniazid, rifampicin, ethambutol, pyrazinamide and streptomycin in culture‐based drug susceptibility testing. We therefore obtained a genomic DNA preparation of VTB1 to enable direct comparison with the TASMDR1 isolate collected in Tasmania. Next generation sequencing of VTB1 was performed on an Illumina platform and paired‐end reads were mapped to the M. tuberculosis H37Rv reference genome (NC_000962.3). The Box shows variants associated with drug resistance. In addition to drug resistance mutations, VTB1 shared all previously described variants in TASMDR1 with respect to H37Rv3 and, therefore, the two isolates were genetically indistinguishable. This is strongly indicative of transmission involving the two patients based on established single nucleotide polymorphism thresholds.4 It is most probable that the patient diagnosed in Tasmania contracted the MDR strain of M. tuberculosis during the episode of pulmonary disease diagnosed in the household contact in 2012 and that the infection remained latent until reactivating as extrapulmonary MDR tuberculosis in 2016. In conclusion, the global burden of latent tuberculosis infection has been estimated to be 23% of the world's population, which corresponds to about 1.7 billion people.5 Despite the immense prevalence of latent tuberculosis infection, there are few reports in the literature that confirm using genome variant analyses for the translocation of the MDR form of tuberculosis from one jurisdiction to another as a latent infection and its subsequent emergence as active MDR tuberculosis in a new host country. This type of transit of tuberculosis is difficult to detect with pre‐immigration screening practices that are reliant upon a diagnosis of pulmonary tuberculosis based on a chest x‐ray. The international movement of MDR tuberculosis in latent form, as has been determined in this case, is an area of concern and could be a significant challenge for future tuberculosis eradication. The growing application of genome sequencing in tuberculosis diagnostics and surveillance will help establish the level of MDR tuberculosis cases due to reactivation of latent tuberculosis infection. Box – Drug resistance determining mutations in a contact who presented with tuberculosis in Vietnam in 2012 (VTB1) and in the first confirmed patient with multidrug‐resistant (MDR) tuberculosis in Tasmania in 2016 (TASMDR1). The isolate from VTB1 and TASMDR1 share identical drug resistance mutations Isolates Drug Gene Function Mutation Substitution VTB1 and TASMDR1 Rifampicin rpoB (Rv0667) RNA polymerase β‐subunit gAc/gGc, tCg/tTg D435G, S450L Isoniazid katG (Rv1908c) Catalase‐peroxidase aGc/aCc S315T Pyrazinamide pncA (Rv2043c) Pyrazinamidase/nicotinamidase cCg/cTg P62L Ethambutol embB (Rv3795) Arabinosyltransferase B Atg/Gtg M306V Streptomycin rrs (MTB000019) 16S ribosomal RNA a/c a514c* * Substitution located in a non‐protein coding gene. ◆

Sanjay S Gautam · Greg Haug · Louise A Cooley · Micheál Mac Aogáin · Ronan F O'Toole