Managing Respiratory Infections in Primary Care and Emerging Antibiotic Resistance David Enoch Consultant Medical Microbiologist Infection Control Doctor Public Health England Tuesday 3 rd November School of Clinical Medicine

Some of the problems of antimicrobial resistance Some local bacterial epidemiology Recommended treatment for common respiratory tract infections What you need to know at the end of this talk

‘In another 20 years the Chest physician as the central figure of tuberculosis control will also have disappeared. And by 2010 tuberculosis itself - with an incidence of 0.2 per 100,000 – will be of no more importance to the community than typhoid fever is today. It will be of interest only to the medical historian.’ Bignall, 1971 Postgraduate Medical Journal ‘It is time to close the book on infectious diseases, and declare the war against pestilence won.’ William H. Stewart, Surgeon General The future is difficult to predict…

Emerging antibiotic resistance; carbapenemases

Acquired resistance absent from bacteria collected before 1940 Resistance repeatedly followed introduction of new antibiotics Resistant mutants selected in therapy Resistance greatest where use heaviest Good evidence that use selects resistance

Correlation between penicillin use and resistance Goossens et al Lancet 2005

Good evidence that use selects resistance

Clostridium difficile

Antibiotic consumption UK · PDF file English surveillance programme for antimicrobial utilisation and resistance

Local data

Local data

Antibiotic consumption UK

Most commonly used antibiotics (community) β-lactams –Penicillin V –Amoxicillin –Co-amoxiclav –Flucloxacillin Tetracyclines –Tetracycline –Doxycycline Macrolides –Clarithromycin –Erythromycin Antifolates –Trimethoprim

Top five reasons for giving antibiotics (community) Respiratory tract infections –Sore throat / pharyngitis –Pneumonia –Bronchitis –(COPD) –(Bronchiectasis) –(Acute otitis media) Urinary tract infections Skin soft tissue infections (cellulitis)

Antibiotic guidelines Based on national Clinical Knowledge Summary recommendations Developed in conjunction with local microbiologists Consider local susceptibility patterns

Antibiotic guidelines

Sore throat / pharyngitis Very common – 120 patients per year for a 2000 patient practice But only 1 in 18 episodes lead to a consultation Viral infections are the commonest cause Common cold(25%) Influenza(4%) Adenovirus (4%) Herpesvirus (2%) EBV (~1%)

Sore throat / pharyngitis Group A strep (GAS) is the commonest bacterial cause: 15-30% in children 10% in adults Self limiting irrespective of whether or not viral within 3 days in 40% of cases within 7 days in 85% of cases

Sore throat / pharyngitis Sore throat / pharyngitis – who will benefit from antibiotic treatment? Cochrane collaboration studies involving 12,835 cases absolute benefit of antibiotics modest shortened duration of symptoms by 16 hours reduced incidence of suppurative complications quinsy, acute OM (by a third) and acute sinusitis (by 50%) natural history of symptoms similar in placebo group regardless of aetiology Risk of complications with or without antibiotic is low for the majority of cases Petersen et al 2007, UK cohort study Number needed to treat to prevent quinsy = 4300 in patients with sore throat

Sore throat / pharyngitis Sore throat / pharyngitis – who will benefit from antibiotic treatment? Apply Centor criteria presence of tonsillar exudate presence of tender anterior cervical lymphadenopathy or lymphadenitis history of fever absence of cough Centor 3 or 4 – 40-60% chance of Group A strep and may benefit from antibiotic Centor 0 or 1 – unlikely to have Group A strep infection (80% chance) and antibiotics is unlikely to be beneficial

Sore throat / pharyngitis Who do you send a sample for?

Sore throat / pharyngitis Who do you send a sample for? UK and US guidelines differ somewhat…

Sore throat / pharyngitis Scotland: Throat swabs should not be carried out routinely in primary care management of sore throat A positive throat culture for GAS makes the diagnosis of streptococcal sore throat likely but a negative culture does not rule out the diagnosis Symptoms also correlate poorly with results of throat swab culture Throat swabs are neither sensitive nor specific for serologically confirmed infection, considerably increase costs, may medicalise illness, and alter few management decisions SIGN guidelines (2010)

How should the diagnosis of GAS pharyngitis be established? US guidelines Swabbing the throat and testing for GAS pharyngitis by rapid antigen detection test (RADT) and/or culture should be performed because the clinical features alone do not reliably discriminate between GAS and viral pharyngitis except when overt viral features like rhinorrhoea, cough, oral ulcers, and/or hoarseness are present In children and adolescents, negative RADT tests should be backed up by a throat culture (strong, high). Positive RADTs do not necessitate a back-up culture because they are highly specific (strong, high). Routine use of back-up throat cultures for those with a negative RADT is not necessary for adults in usual circumstances, because of the low incidence of GAS pharyngitis in adults and because the risk of subsequent acute rheumatic fever is generally exceptionally low in adults with acute pharyngitis (strong, moderate). Physicians who wish to ensure they are achieving maximal sensitivity in diagnosis may continue to use conventional throat culture or to back up negative RADTs with a culture Anti-streptococcal antibody titres are not recommended in the routine diagnosis of acute pharyngitis as they reflect past but not current events; (strong, high)

Who Should Undergo Testing for GAS Pharyngitis? USA Testing for GAS pharyngitis usually is not recommended for children or adults with acute pharyngitis with clinical and epidemiological features that strongly suggest a viral aetiology (e.g. cough, rhinorrhoea, hoarseness, and oral ulcers; strong, high) Diagnostic studies for GAS pharyngitis are not indicated for children <3 years old because acute rheumatic fever is rare in children <3 years old and the incidence of streptococcal pharyngitis and the classic presentation of streptococcal pharyngitis are uncommon in this age group Selected children <3 years old who have other risk factors, such as an older sibling with GAS infection, may be considered for testing (strong, moderate) Follow-up post-treatment throat cultures or rapid antigen detection test (RADT) are not recommended routinely but may be considered in special circumstances (strong, high) Diagnostic testing or empiric treatment of asymptomatic household contacts of patients with acute streptococcal pharyngitis is not routinely recommended (strong, moderate) Shulman ST et al Clin Infect Dis. 2012; 55: e86-102

Rapid antigen detection tests (RADT) Various results in meta-analyses Sensitivities between 59 and 95% and specificities over 90% Don’t differentiate between carriage and disease Take about 10 minutes Wide variation in test methods Optical immunoassay ELISA FISH PCR Wide variation in test performance Wide variation in costs Quality control ‘Insufficient evidence at present to support their use’ (SIGN 2010)

Sore throat / pharyngitis Penicillin V Narrow spectrum β-lactam agent Main issue is erratic absorption – rapidly but incompletely absorbed Has activity against streptococci including Group A streptococci Not active against penicillinase producers Staphylococcus aureus Only indicated for sore throat (pharyngitis) Do not use in severe disease or in the systemically unwell

Acute chest infections Acute bronchitis acute inflammation of the bronchial tree associated with oedema and mucus production leading to cough and phlegm production that lasts for up to 3 weeks Community acquired pneumonia (CAP) acute infection of the lung parenchyma. Infective exacerbations of chronic obstructive pulmonary disease (COPD) Cough is the predominant symptom for acute bronchitis and community- acquired pneumonia (CAP) Difficult to distinguish CAP from acute bronchitis

Acute chest infections

Acute bronchitis Provide self-care advice: hydration, analgesia, and comfort measures. People who smoke should be encouraged to quit Antibiotics are not routinely indicated ◦ Consider prescribing an antibiotic if the person has a significantly impaired ability to fight infection (e.g. immunocompromised status, cancer, or physical frailty) or if acute bronchitis is likely to significantly worsen a pre-existing condition (e.g. heart failure, angina, or diabetes) If an antibiotic is necessary, prescribe amoxicillin first-line, or doxycycline as an alternative Consider a macrolide (erythromycin or clarithromycin) if amoxicillin or doxycycline are unsuitable ◦ A delayed antibiotic prescribing strategy may be considered Co-amoxiclav or doxycycline are options in people who have already received amoxicillin CKS NICE guidelines

Community acquired pneumonia Community- acquired Pneumonia Key bacterial pathogens are Streptococcus pneumoniae39% Haemophilus influenzae5.2% Legionella pneumophila3.6% Staphylococcus aureus1.9% Atypicals10.8% Antibiotics are always indicated for patients with pneumonia

Respiratory tract infections Table 1. Antibiotic susceptibility of S. pneumoniae Organism % susceptible Pen Fluclox Ery Tetra Cipro S. pneumoniae Table 2. Antibiotic susceptibility of Gram-negative sputum isolates Organism% susceptible Amox Co-amox Ery Tetra Cipro Trim H. influenzae Moraxella catarrhalis P. aeruginosa

Respiratory tract infections Microbiological investigations Usually not necessary to diagnose CAP or acute bronchitis managed in community. Sputum samples for culture and/or sensitivity may be useful in people with: Recurrent episodes of acute bronchitis who may have become colonized with bacteria resistant to first-line antibiotics.

Community acquired pneumonia Use the CRB65 score to stratify patient’s risk of death CRB65 = 0:low risk – treatment at home CRB65 = 1 or 2:intermediate risk – consider same day assessment in hospital CRB65 = 3 or 4:high risk – urgent admission C – confusion R – respiratory rate of ≥30 breaths/min B – blood pressure — systolic of ≤90 mmHg or diastolic of ≤60 mmHg ≥65 years old If available, use pulse oximetry to assess the severity of people with suspected pneumonia and other acute respiratory illnesses People with oxygen saturation less than 92% require admission to hospital

Community acquired pneumonia Community-acquired Pneumonia Choice of antibiotic Based on low prevalence of penicillin resistance among pneumococcus First line CRB65 score of 0 – amoxicillin CRB65 score of 1 and at home – amoxicillin plus clarithromycin Second line CRB65 score of 0 or 1 and at home – doxycycline (2 nd line agent) If no response at 48 hours in patients on amoxicillin Consider adding clarithromycin

Respiratory infections What is the clinical evidence for single therapy treatment for CAP? limited literature available for low severity CAP only one RCT compared clarithromycin with or without cefuroxime no difference in mortality or complications reported Amoxicillin is the current UK standard has advantage of amoxicillin over macrolides reduction in mortality fewer withdrawal from adverse events in studies

Respiratory infections What is the clinical evidence for single therapy treatment for CAP? Co-amoxiclav compared with clarithromycin more treatment discontinuation due to adverse event in the β-lactam arm Azithromycin clinically favoured over erythromycin in one RCT mortality, clinical cure and withdrawal due to adverse events

Respiratory infections Are there biomarkers you could use in General Practice to help differentiate viral from bacterial LRTI?

Respiratory infections Are there biomarkers you could use in General Practice to help differentiate viral from bacterial LRTI? Yes! CRP Procalcitonin

C ‑ reactive protein (CRP) Consider a point of care C ‑ reactive protein test if after clinical assessment a diagnosis of pneumonia has not been made and it is not clear whether antibiotics should be prescribed Use the results of the CRP test to guide antibiotic prescribing in people without a clinical diagnosis of pneumonia as follows: Do not routinely offer antibiotic therapy if the CRP concentration is <20 mg/L Consider a delayed antibiotic prescription (a prescription for use at a later date if symptoms worsen) if the CRP concentration is between 20 – 100 mg/L Offer antibiotic therapy if the CRP concentration is >100 mg/L NICE guidelines

C ‑ reactive protein and procalcitonin NICE guidelines Three RCTs examining the addition of CRP testing to usual care to guide antibiotic prescription in patients presenting to primary care with LRTI were considered These showed a significant reduction in antibiotic prescription rates in the CRP group compared with usual care both at the index consultation and within 28 days One systematic review examining the addition of PCT testing to usual care to guide antibiotic prescription was considered. There was a significant reduction in antibiotic prescription rates across all settings CRP had a stronger correlation with consolidation on CXR than PCT or clinical judgement alone CRP is considerably cheaper than PCT (£12-15 compared with £25-35) when considering the cost of tests

C ‑ reactive protein and procalcitonin NICE guidelines Potential problems Costs Antibiotic course versus CRP test Reagents Who does the test? Quality assurance

COPD Prescribe oral antibiotics for people with purulent sputum or clinical signs of pneumonia depending on local antibiotic prescribing guidelines ◦Prescribeamoxicillin 500 mg tds5 days ordoxycycline 200 mg, then 100 mg od 5 days ◦If amoxicillin and doxycycline are contra-indicated, prescribe clarithromycin 500 mg bd5 days ◦If the person has an increased risk of antibiotic resistance (comorbid disease, severe chronic obstructive pulmonary disease [COPD], frequent exacerbations, or antibiotic use in the past 3 months) co-amoxiclav 500/125 mg tds5 days

Differential diagnosis If ‘acute bronchitis’ and cough persists longer than 3 weeks rule out: Asthma / chronic obstructive pulmonary disease. Post-infectious cough Whooping cough Post-nasal drip Gastro-oesophageal reflux Tuberculosis An underlying malignancy

Some cases (based on results)

Cases

Summary Antibiotics are a precious resource Community prescribing mostly for respiratory tract, urine and skin infections Narrow spectrum antibiotics if possible Short periods of treatment Rapid / POCT may be worthwhile Rationalise when possible, based on susceptibility results Consider delayed prescribing where possible If recurrent infections, address underlying source

Summary

Acknowledgements Sani Aliyu Fiona Cooke Please remember that antibiotics are needed to treat infections…