strategy might be as beneficial as immediate prescription. However, we do not support a delayed prescription strategy, for the following reasons. Guidelines from the UK National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network state that “antibiotics should not be used to secure symptomatic relief in sore throat”. Moreover, delayed prescription shifts responsibility to patients.2 Additionally, in a previous study by Little and colleagues, 3 quinsy occurred in 30 (0·5%) of 5932 patients who were given antibiotics compared with 11 (0·2%) of 4974 who were not given antibiotics. This ﬁnding needs more explanation and could be used to support the argument against intake of antibiotics. We agree with the Comment2 by Benedikt Huttner that Little and colleagues’ cohort study 1 is prone to confounding—eg, the types of antibiotics prescribed are unknown. Furthermore, information about what proportion of patients actually took their prescribed antibiotics (delayed or immediate prescriptions) is not provided. However, most importantly, most studies into antibiotics for sore throat have reported that the greatest improvement of symptoms occurs 3 or 4 days after treatment begins (for the 20% patients with a proven group A β-haemolytic streptococcal pharyngitis). 4,5 Thus, delaying antibiotics by 48 h or more would overshoot this period.4 We agree with diﬀerent European guidelines for acute sore throat, which recommend antibiotics only for very ill or immunocompromised patients (about 5% of patients with acute sore throat, which is far fewer than would receive antibiotics in a delayed prescription strategy). 5 To achieve the least amount of antibiotic use—in the absence of risk to the patient—doctors should use a noantibiotics strategy with advice to 920
return to the clinic if symptoms do not resolve.4,5 Paracetamol (or nonsteroidal anti-inflammatory drugs) taken every 4 h for an extra 1–2 days could replace unnecessary antibiotic use in most patients and might reduce antibiotic resistance. The best strategy to reduce antibiotic use for acute sore throat is to motivate doctors not to prescribe antibiotics, instead of putting this responsibility on the shoulders of patients. We declare no competing interests.
*Jan Matthys, Marc De Meyere [email protected]
University of Ghent, De Pintelaan 185, Ghent 9000, Belgium 1
Little P, Stuart B, Hobbs FD, et al, for the DESCARTE investigators. Antibiotic prescription strategies for acute sore throat: a prospective observational cohort study. Lancet Infect Dis 2014; 14: 213–19. Huttner B. Antibiotic prescription for sore throat or the legacy of Mr X2. Lancet Infect Dis 2014; 14: 177–78. Little P, Stuart B, Hobbs FD, et al, for the DESCARTE investigators. Predictors of suppurative complications for acute sore throat in primary care: prospective clinical cohort study. BMJ 2013; 347: f6867. Spurling GK, Del Mar CB, Dooley L, Foxlee R, Farley R. Delayed antibiotics for respiratory infections. Cochrane Database Syst Rev 2013; 4: CD004417. Matthys J, De Meyere M, van Driel ML, De Sutter A. Diﬀerences among international pharyngitis guidelines: not just academic. Ann Fam Med 2007; 5: 436–43.
Author’s reply Jan Matthys and Marc De Meyere’s have several criticisms of our paper. First, with respect to their comment that delayed prescription shifts the responsibility to patients, one of the reasons delayed prescription is likely to be effective is because it shifts some responsibility to patients, who are also satisfied with the approach.1,2 It reduces both patients’ belief in antibiotics and reconsultations,1,2 and reconsultations often result in an antibiotic prescription. The fact that in our previous study quinsy occurred in numerically more patients who were given antibiotics than those who were not is not unusual: the crude figures do not
take into account confounding by indication, which our current paper does. We agree that our study was prone to confounding, but when the factors that predict prescription are well documented (as in our current study), propensity scores can usefully correct for confounding by indication. Residual confounding is always possible, but the direction and magnitude of the change in estimates using propensity scores would suggest that the effect of residual confounding, if anything, would be to underestimate the beneﬁt of delayed prescribing. The assertion that the time of greatest benefit for symptoms is 3–4 days after treatment does not seem to be supported by the results of a Cochrane review,3 which show that the greatest risk reduction in absolute and relative terms occurs at day 7 not day 3, and an even greater diﬀerence in risk ratios at day 7 for those with, compared with those without, streptococcal infection. With respect to guidelines’ suggestions that antibiotics should only be used in very ill or immunocompromised patients, we agree that antibiotics are mostly not necessary for symptom control, but the definition of “very ill” is subjective. Data suggest that when a doctor is concerned about the risk of complications or severe symptoms and is considering prescribing antibiotics, delayed antibiotics can be useful, and can reduce reconsultations and complications, compared with a no-prescription strategy. This accords with the UK National Institute for Health and Care Excellence (NICE), 4 which supports delayed prescription as a cost-effective strategy, and NICE guidance has the dual advantages of both a systematic scientiﬁc literature review and economic modelling to inform policy, unlike many guidelines. I declare no competing interests.
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Paul Little, on behalf of the DESCARTE investigators University of Southampton, Aldermoor Health Centre, Southampton SO16 5ST, UK 1
Little PS, Williamson I, Warner G, Gould C, Gantley M, Kinmonth AL. An open randomised trial of prescribing strategies for sore throat. BMJ 1997; 314: 722–27. Little PS, Gould C, Williamson I, Warner G, Gantley M, Kinmonth AL. Reattendance and complications in a randomised trial of prescribing strategies for sore throat: the medicalising eﬀect of prescribing antibiotics. BMJ 1997; 315: 350–52. Spinks A, Glasziou P, Del Mar C. Antibiotics for sore throat. Cochrane Database Syst Rev 2013; 11: CD000023. Tan T, Little P, Stokes T. Antibiotic prescribing for self limiting respiratory tract infections in primary care: summary of NICE guidance. BMJ 2008; 337: a437.
Fungal meningitis in England and Wales Ifeanichukwu Okike and colleagues,1 in their work on trends in bacterial, mycobacterial, and fungal meningitis diagnosed over 8 years in England and Wales, probably underestimated the real incidence of fungal meningitis. We were surprised to read that only Candida (albicans and non-albicans) meningitis was recorded on the basis of positive cerebrospinal ﬂuid or blood cultures in patients with a clinical diagnosis of meningitis. The investigators made no mention of Cryptococcus neoformans—a yeast that is easy to culture from blood and cerebrospinal fluid. Moreover, C neoformans is actually thought to be the main cause of fungal meningitis worldwide, with the highest burden in sub-Saharan Africa (about 650 000 cases per year). HIV infection is the underlying disease associated with cryptococcal meningitis in 70–80% of cases, but cryptococcal meningitis is reported in patients with other causes of immunodeficiency as well. 2 Although the introduction of effective antiretroviral therapy was characterised by a decrease in the incidence of AIDS-associated cryptococcal meningitis, this type www.thelancet.com/infection Vol 14 October 2014
of meningitis remains an important opportunistic infection in patients with HIV. 3 Results from a cohort study4 from ten of the largest UK HIV centres showed that the incidence of cryptococcal meningitis was 0·5 per 1000 person-years in 2004–05 and 0·2 per 1000 person-years in 2006–07. Moreover, of 157 patients in a southwest London cohort5 presenting between 2004 and 2010 with newly diagnosed HIV infection, seven (4%) had cryptococcal meningitis. In an analysis of 18 US states using US inpatient databases, 6 30 840 admissions to hospital for cryptococcal meningitis were documented over 13 years (1997–2009) with an estimated 3400 admissions to hospital per year associated with cryptococcal meningitis in the USA. Incidences of 0·1, 0·2, or 0·5 per 100 000 people applied to the population of England and Wales (56 567 800 people according to the mid-2012 census) would yield 56, 113, or 282 cases, respectively, of cryptococcal meningitis per year in England and Wales. During the 8 years assessed in Okike and colleagues’ study 1 (2004–11), a minimum of 448 and a maximum of 2256 cryptococcal meningitis infections are estimated to have occurred according to these incidence rates. Two more points about the Article deserve to be discussed. First, the median age of patients with Candida spp meningitis was 40·4 years and only 12% of cases were reported in children, which is unexpected. Candida meningitis is usually the result of haematogenous dissemination of the fungus in premature newborn babies with very low weight. The absence of any clinical data about affected patients makes any consideration about risk factors (eg, CNS surgery, ventriculoperitoneal or ventriculoatrial shunt infection, cancer) impossible in this older population. Second, except for
cryptococcal meningitis, the diagnosis of fungal meningitis by traditional microbiological methods (ie, cerebrospinal culture) is generally difficult and characterised by low sensitivity. In the case of candida meningitis, a review 7 reported a sensitivity of 44% for the initial culture, increasing to 83% for serial cultures. We would be interested to know how many patients in Okike and colleagues’ study 1 had a clinical diagnosis of candida meningitis made only by positive blood culture. Finally, in view of the abovementioned problems encountered in correctly diagnosing fungal meningitis, the use of galactomannan antigen, 1,3-β-D-glucan antigen, mannan antigen, and anti-mannan antibodies in cerebrospinal fluid is highly recommended. We declare no competing interests.
*Spinello Antinori, Anna Maria Peri, Laura Milazzo [email protected]
Dipartimento di Scienze Biomediche e Cliniche Luigi Sacco, Università degli Studi di Milano, Italy 1
Okike IO, Ribeira S, Ramsay ME, Heath PT, Sharland M, Ladhani SN. Trends in bacterial, mycobacterial, and fungal meningitis in England and Wales 2004–11: an observational study. Lancet Infect Dis 2014; 14: 301–07. Antinori S. New insights into HIV/AIDSassociated cryptococcosis. ISRN AIDS 2013; 2013: 471363. Antinori S, Ridolfo AL, Fasan M, et al. AIDS-associated cryptococcosis: a comparison of epidemiology, clinical features and out come in the pre-and post-HAART eras. Experience of a single centre in Italy. HIV Med 2009; 10: 6–11. The UK Collaborative HIV Cohort (CHIC) Study Steering Committee. HIV-associated central nervous system diseases in the recent combination antiretroviral therapy era. Eur J Neurol 2011; 18: 527–34. Patel S, Shin GY, Wijewardana J, et al. The prevalence of cryptococcal antigenemia in newly diagnosed HIV patients in a southwest London cohort. J Infect 2013; 66: 75–79. Pyrgos V, Seitz AI, Steiner CA, Prevots DR, Williamson PR. Epidemiology of cryptococcal meningitis in the US: 1997–2009. PLoS One 2013; 8: e56269. Voice RA, Bradley SF, Sangeorzan JA, Kauﬀman CA. Chronic candidal meningitis: an uncommon manifestation of candidiasis. Clin Infect Dis 1994; 19: 60–66.