JAC Advance Access originally published online on September 9, 2009
Journal of Antimicrobial Chemotherapy 2009 64(5):889-894; doi:10.1093/jac/dkp313
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Leading articles |
Swine flu and antibiotics
Department of Infection & Tropical Medicine, Castle Hill Hospital, Hull & East Yorkshire Hospitals NHS Trust, Cottingham, East Yorkshire HU16 5JQ, UK
* Tel: +44-01482-875875, ext. 2267; Fax: +44-01482-622494; E-mail: Gavin.Barlow{at}hey.nhs.uk
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Abstract |
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Health services worldwide are likely to be hard-pressed by swine flu-related illness in the months ahead. Secondary infections with Streptococcus pneumoniae, other streptococci (e.g. Streptococcus pyogenes), Haemophilus influenzae and Staphylococcus aureus are likely to be important causes of morbidity and mortality. The UK Department of Health recently published clinical pathways for the management of swine flu. Suggested severity criteria have not been validated in respiratory infection and are different from those previously published. Antibiotics are recommended for all patients assessed at hospital, regardless of severity of illness; cephalosporins or quinolones are suggested for inpatients with pneumonia. These recommendations will jeopardize recent decreases in Clostridium difficile-associated diarrhoea (CDAD) and methicillin-resistant S. aureus (MRSA) in UK hospitals. This article, written on behalf of the BSAC Council, considers these recommendations and provides alternative antibiotic regimens for a range of clinical scenarios.
Keywords: influenza , pneumonia , lower respiratory tract infections
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Introduction |
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Since the WHO declared a global influenza pandemic on 11 June 2009, it has become clear that health services in the UK and worldwide are likely to be hit by a tidal wave of flu-related illness in the months ahead, as has already occurred in Mexico.1 Secondary bacterial infections, particularly with Streptococcus pneumoniae, other streptococci (e.g. Streptococcus pyogenes), Haemophilus influenzae and Staphylococcus aureus are likely to be important causes of morbidity and mortality.2 The UK Department of Health (DoH) recently published pathways for the clinical management of swine flu that include advice on antibiotic prescribing.3 The adult hospital pathway starts by recommending seven criteria (Table 1) upon which the site-of-care decision (i.e. inpatient versus outpatient) should be based. Although accurate assessment of severity of illness is undoubtedly the key critical process when making decisions about antibiotic therapy and other aspects of care for infections, the DoH pathway recommends an antibiotic for all patients, regardless of severity assessment or whether secondary bacterial infection is likely. This article, written on behalf of the BSAC Council, considers these recommendations and suggests alternative antibiotic strategies and regimens that hospitals and healthcare staff could employ during the pandemic.
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Severity assessment |
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The DoH severity criteria (Table 1) have not been validated in respiratory infection and are different from those (the CURB-65 criteria) recommended in existing guidelines for the management of influenza-associated pneumonia,2 the development of which were supported by the DoH. CURB-65 (Table 1), which has been validated in multiple studies internationally as having moderate performance in the prediction of mortality in community-acquired pneumonia (CAP),4–7 is simple and widely recognized and used in the UK, and in other countries. This is important, as familiarity with pneumonia severity criteria has previously been shown to be poor in the UK.8 CURB-65 also appears to be useful in predicting mortality in non-respiratory infections.9 The pathway's criteria for admission to hospital and subsequent management strategies are set at a high threshold, presumably aimed at peaks of activity when admission to hospital may have to be ‘rationed’. However, either side of such peaks or if the pandemic places a lower burden on hospitals than expected, these criteria could lead to unnecessary mortality by denying access to hospital care. That physiological signs can deteriorate late (i.e. close to death) in young patients with serious illness, including pneumonia, is a common concern expressed by experienced clinicians.10 The DoH criteria do not consider co-morbidity or pre-morbid functional status, which are important considerations in the site-of-care decision.11 Application of the DoH criteria in determining the need for inpatient care could be considered as being below the standard of acceptable clinical practice.
Severity assessment should be based on existing familiar criteria,2,4,12 although these should be prospectively validated, and if necessary modified, during the pandemic. Early evidence from the UK and elsewhere suggests that asthma requiring medication, obesity and pregnancy are common risk factors for life-threatening illness and that hypoxia (often with a normal chest radiograph), hypotensive shock and confusion are the key clinical signs of severe infection.13 Other risk factors and severity criteria are likely to emerge as the pandemic progresses.
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Antibiotics |
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The advocated ‘broad-brush’ approach to antibiotic prescribing during a pandemic is in sharp contrast to usual clinical practice for seasonal influenza and will undermine the considerable antibiotic stewardship achievements that have contributed to decreases in Clostridium difficile-associated diarrhoea (CDAD) and methicillin-resistant S. aureus (MRSA) in many UK hospitals. An increase in such problems during a pandemic is likely to place an additional burden on health services at a time of extreme strain. The antibiotic guidance also contradicts the existing guidelines (to which the DoH contributed), which advocate a more selective approach (Table 2).2 Hospitalization and mortality rates due to swine flu in the UK do not currently warrant widespread antibiotic prescribing, although the threshold for prescribing may have to change if the swine flu virus evolves to become more virulent. The lack of consistency between existing DoH guidelines will cause confusion in healthcare professionals and unnecessary variation in clinical practice. The widespread use of antibiotics during a pandemic for patients who do not need them could also jeopardize the availability of a vital resource for patients who do.
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Later in the pathway, a ‘broad-spectrum cephalosporin or quinolone (clarithromycin may be added)’ is recommended for all hospitalized patients with pneumonia. Specific agents, doses and the intended route of administration are not provided. Cephalosporin and quinolone antibiotics have been strongly associated with CDAD and MRSA,14,15 and have therefore been decreasingly used in UK hospitals in recent years, in adherence with the DoH guideline ‘Clostridium difficile infection: how to deal with the problem’.16 There is no high quality evidence that cephalosporins or respiratory fluoroquinolones are more clinically effective or cost-effective in respiratory infections compared with other agents. This recommendation also assumes that all hospitalized patients will be severely ill, which may not be the case. If clinicians follow this recommendation, a considerable number of patients will receive unnecessarily broad-spectrum therapy.
The term ‘quinolone’ is confusing because the most commonly used quinolone antibiotic in the UK is ciprofloxacin. This is not a respiratory quinolone and has suboptimal activity against S. pneumoniae. Although existing guidelines recommend ‘a fluoroquinolone with enhanced activity against pneumococci’ (in the UK, levofloxacin or moxifloxacin),2 the DoH and hospitals should be cautious in advocating these agents as they have also been associated with CDAD,17 and an increasing proportion of methicillin-susceptible S. aureus (MSSA) (e.g. 30% in Hull and East Yorkshire) and almost all MRSA are now resistant to fluoroquinolones.
So what antibiotics should be prescribed and when during a pandemic? The answer to this depends on several factors, including whether the patient has symptoms, signs or investigation results suggestive of secondary bacterial infection, how ill the patient is, the likely causal pathogen(s), the local epidemiology of antibacterial resistance and a patient's individual risk of adverse effects such as CDAD. The likelihood of bacterial infection should be based on accepted existing criteria for the diagnosis of bacterial respiratory infections and infective exacerbations of co-morbidities, in particular underlying respiratory disease [e.g. chronic obstructive pulmonary disease (COPD)].12,18 If the swine flu virus becomes more virulent, with a higher incidence of secondary bacterial infection and mortality, the threshold for diagnosing secondary bacterial infection may need to be lowered. An important emerging theme in the UK is the considerable overdiagnosis of swine flu and overprescription of oseltamivir, which in some hospitalized cases has led to the delayed diagnosis of other life-threatening infections such as tuberculosis and endocarditis (R. A. Seaton, Gartnavel Hospital, Glasgow, personal communication; the author's own unpublished observations).
Severity assessment has been discussed above. The bacteria of secondary infection are relatively predictable, with S. pneumoniae, other streptococci, H. influenzae and S. aureus the most likely culprits. The experience of BSAC Council members so far has been that secondary bacterial infection is infrequent, but that when it has occurred, S. pneumoniae and S. pyogenes have been implicated. The latter is always susceptible to penicillin, and high-level penicillin resistance in S. pneumoniae is rare in the UK. Clindamycin, which has toxin-suppressing properties, should be added to benzylpenicillin in patients with proven, life-threatening S. pyogenes infection.19 There is little evidence about the impact the atypical pneumonia bacteria might have, although co-infection with other respiratory bacteria and viruses is well recognized.20 S. aureus rarely causes minor respiratory tract infections (i.e. infections are usually severe) so it is debatable as to whether it needs to be covered in patients with mild illness managed by general practitioners or as outpatients.21 Nevertheless, clinicians may feel uncomfortable, in the context of a pandemic, not covering staphylococci, so doxycycline is a reasonable choice for oral therapy as suggested in existing guidelines, with co-amoxiclav or macrolides as alternative agents for specific circumstances (e.g. children, pregnancy); see Table 3 for potential antibiotic regimens. There is some doubt about the activity of some macrolides against H. influenzae in vivo,22 so it may be best to reserve these as alternative or second-line agents in those with underlying respiratory disease.
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Broadly, there are likely to be three cohorts of patients admitted to hospital with influenza-related illness at the peak of the pandemic: those requiring critical care (whether a bed is available or not); those likely to have a bacterial infection, but who do not require critical care; and those admitted due to complications such as bronchospasm or poor social circumstances, but with no or limited evidence of bacterial infection; the latter patients should not receive antibiotics. The most common presentation will be with respiratory illness. Those requiring critical care will have the highest mortality and the most to lose by receiving suboptimal therapy; they should be treated with broad-spectrum respiratory antibiotics according to current national recommendations for severe CAP.2,12 If microbiological investigations are positive, antibiotics should be streamlined to the narrowest spectrum possible (e.g. from co-amoxiclav/macrolide dual therapy to benzylpenicillin monotherapy in patients with S. pneumoniae infection).23
Those with bacterial infection but who do not require critical care are likely to be the largest cohort of inpatients. For those able to take oral therapy, doxycycline covers a broad range of respiratory pathogens, is taken once or twice daily and is generally considered to be less likely to cause CDAD than co-amoxiclav or combination regimens.24 For non-critical care patients requiring intravenous (iv) therapy, a macrolide alone or in combination with flucloxacillin is less likely to cause CDAD than broader spectrum regimens, although co-amoxiclav or other agents may need to be considered for patients at risk of H. influenzae infection. Other agents, such as trimethoprim, co-trimoxazole and tigecycline, may have useful roles in specific circumstances. Length of therapy is also an important predictor of CDAD and the emergence of antibiotic resistance.10,25 In uncomplicated, non-critical care patients, 5–7 days of oral therapy will suffice in most patients.26 In severe pneumonia initially treated with iv antibiotics, patients should be switched to oral therapy as soon as clinical stability has occurred, in keeping with published evidence.27,28
Local epidemiological factors, such as the pattern of antibacterial resistance in MSSA and other respiratory bacteria, and the incidence of community-associated MRSA also need to be considered and reviewed as the pandemic evolves. It is well recognized that older patients are more likely to get CDAD, so alternative prescribing strategies, using effective but lower risk regimens, may be warranted in this and other CDAD high risk groups.10 Particularly for sicker patients, clinicians may also wish to consider the theoretical non-antibacterial effects of some antibiotics; for example, doxycycline has been shown to have potentially useful immune modulation properties and macrolide-containing regimens have been shown to improve outcomes in some studies of severe bacteraemic pneumococcal pneumonia.29,30
To be used widely and provide a consistent standard of healthcare during a pandemic, national recommendations must be simple and easy to implement, adaptable to local circumstances, trusted by clinicians, be based on existing practice, evidence and guidelines (whenever possible), and have the necessary flexibility to account for emerging research evidence and evolution, in whatever direction, of the pandemic. This is not the case for the current DoH adult hospital pathway for swine flu. Until revised, clinicians and hospitals will be better served using existing guidance and adapting their clinical practice, if needed, from a starting point of what they consider to be the current minimum standards of care.
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Transparency declarations |
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G. D. B. has received support to attend conferences/meetings from Sanofi-Aventis, Gilead, Pfizer, Chiron and Janssen Cilag, received honoraria for speaking/DVD development from Sanofi-Aventis, and served on an advisory board for Wyeth (UK tigecycline).
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Acknowledgements |
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Members of BSAC Council: L. Piddock, P. Davey, M. Dryden, M. Logan, I. Morrissey, N. Brown, R. Howe, C. Jamieson, V. Weston, A. White, A. Seaton, B. Jones, M. Heginbothom, H. Webb, K. Gould, G. Barlow, K. Hand, C. McNulty, A. Johnson and R. Finch.
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1 Chowell G, Bertozzi SM, Colchero MA, et al. Severe respiratory disease concurrent with the circulation of H1N1 influenza. N Engl J Med (2009) doi:10.1056/NEJMoa0904023.
2
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4
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  M. Eisenhut Comment on: Swine flu and antibiotics J. Antimicrob. Chemother., November 6, 2009; (2009) dkp415v1. [Full Text] [PDF]
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