Cardiovascular diseases

In reply

Bruce CV Campbell

In reply

David B Brieger · James Weaver · Leonard Kritharides

To the Editor: Infective endocarditis with Staphylococcus aureus is associated with a high mortality despite optimal antibiotic therapy.1 The synergy between bacteriophages and antibiotics has been shown in vitro and in animal studies,2 and bacteriophages have demonstrated their value in severe bacterial infections.3 AB‐SA01 (AmpliPhi Biosciences) is a bacterial DNA‐free and protein‐free highly purified preparation of three obligately lytic Myoviridae, each at 109 plaque‐forming units per dose.4 This preparation has been recently used successfully for staphylococcal sinusitis by local irrigation.5 A protocol was established for bacteriophage therapy as an adjunct to standard care of severe staphylococcal infections under the auspices of the Therapeutic Goods Administration Special Access Scheme. Here, we report the first intravenous use of AB‐SA01 in a case of severe staphylococcal sepsis with prosthetic valve endocarditis. A 65‐year‐old man with a 30‐year‐old mechanical aortic valve presented with a week of malaise, severe exertional dyspnoea, and central pleuritic chest pain. He had been successfully treated for Haemophilus aphrophilus aortic valve endocarditis 8 years earlier with antibiotics alone. Examination revealed fever, tachypnoea, tachycardia and borderline hypotension (90–100 mmHg systolic), with a praecordial systolic murmur and click. There was no cardiac, renal or hepatic failure or any evident peripheral embolic sequelae of endocarditis (haematuria, splinter haemorrhages) at this stage. Blood cultures repeatedly grew an identical methicillin‐sensitive S. aureus determined by whole genome sequencing, and the patient received high dose intravenous flucloxacillin, ciprofloxacin and rifampicin (Box). Transoesophageal echocardiography confirmed vegetations on prosthetic aortic and native mitral valves, and the aortic root was thickened with possible paravalvular root abscess. Scheduled cardiopulmonary bypass for operative source control was postponed after a haemorrhagic infarction in the distribution of the left anterior cerebral artery on day −7 (ie, a week before starting bacteriophage therapy), despite concerns regarding development of an aortic root abscess, ongoing fevers and hypotension. Intravenous AB‐SA01 was administered twice a day for 14 days in conjunction with the patient's prescribed antibiotics, commencing (Day 1) 9 days after his first positive blood culture. Blood cultures were negative at onset of bacteriophage therapy, and the C‐reactive protein, temperature, and white cell count results showed downward trends within 24 hours (Box). This trajectory was only interrupted by splenic infarction and occlusion of the superior mesenteric artery 48 hours after commencement, which was proven on computed tomography scan (not shown). No fevers, tachycardia, hypotension or rashes were detected after bacteriophage infusions and no adverse sequelae were attributable to the therapy. The patient recovered after 40 days of antibiotic therapy and returned to his home state for follow‐up. A positron emission tomography scan on Day 80 showed no fluorodeoxyglucose‐avid lesions, including intracardiac lesions. Repeat echocardiogram on Day 98 for progressive heart failure showed severely dilated left ventricle with moderate mitral and trivial aortic regurgitation. A possible mechanical aortic valve vegetation and paravalvular phlegmon were again demonstrated. Blood cultures were negative. He declined surgical intervention and died on Day 103. To our knowledge, this was the first case of staphylococcal prosthetic valve endocarditis treated with intravenous bacteriophage (AB‐SA01), which complies with good manufacturing practice standards.4 Bacteriophage infusions were well tolerated. Future controlled trials are needed to evaluate adjunctive bacteriophage therapy, especially when surgical intervention is not feasible. Box – Graphical representation of antimicrobial treatment, bacteriophage therapy and inflammatory markers − = negative blood cultures; + = positive blood cultures; CRP = C‐reactive protein; SMA = superior mesenteric artery; WCC = white cell count. ◆

Timothy Gilbey · Josephine Ho · Louise A Cooley · Aleksandra Petrovic Fabijan · Jonathan R Iredell

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