Comment
protection against diarrhoea associated with ST-only ETEC or all-cause diarrhoea was seen. Supplemented by Behrens and colleagues’ findings,1 the weight of evidence suggests the need to include other antigens in addition to an LT-based component to achieve enough protection against ETEC diarrhoea to have a positive effect on public health. Our understanding of ETEC pathogenesis continues to develop, and novel target antigens have been identified and need to be fully assessed in relevant animal models and moved rapidly to the field for testing.10 We encourage Behrens and colleagues to present more complete data from this trial. For example, more might be learned from advanced cellular and humoral immunological study of available samples to identify a correlate of protection. Furthermore, the potential of an ETEC vaccine to prevent both the acute disease and the chronic consequences such as postinfectious irritable bowel syndrome, which some studies have shown to be associated with travellers’ diarrhoea,11 has yet to be fully appreciated from the phase 3 data. A preliminary positive signal was noted from the phase 2 LT-patch study,12 when at the 6 month follow-up none of the eight assessable participants in the LT-vaccine group who had diarrhoea developed incident irritable bowel syndrome, whereas three of 17 participants in the placebo group did develop the disorder (although this difference was nonsignificant). If such an association were to hold true in the phase 3 results, the potential value of an ETEC vaccine in a traveller target population could rise substantially. We believe that the future of ETEC vaccine research has brightened with coalescence of a broad interest across the global health community, industry, and academia. The synergy between these partners will hopefully continue to push basic and applied research forward, and
advance vaccine candidates expeditiously through clinical assessment. *Mark S Riddle, Stephen J Savarino Naval Medical Research Center, Silver Spring, MD 20910, USA [email protected] We declare that we have no conflicts of interest. Both authors are employees of the US Government or military service members. The views expressed are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government. Copyright protection is not available for any work of the US Government. 1
2
3
4 5
6
7
8
9 10 11 12
Behrens RH, Cramer JP, Jelinek T, et al. Efficacy and safety of a patch vaccine containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala. Lancet Infect Dis 2013; published online Nov 29. http://dx.doi.org/10.1016/S1473-3099(13)70355-4. PATH, BIO Ventures for Global Health. The case for investment in enterotoxigenic Escherichia coli vaccines. PATH, BIO Ventures for Global Health, 2011. http://www.path.org/publications/files/VAC-etec-investmentrpt.pdf (accessed Nov 6, 2013). Clemens JD, Sack DA, Harris JR, et al. Cross-protection by B subunit-whole cell cholera vaccine against diarrhea associated with heat-labile toxin-producing enterotoxigenic Escherichia coli: results of a large-scale field trial. J Infect Dis 1988; 158: 372–77. Peltola H, Siitonen A, Kyrönseppä H, et al. Prevention of travellers’ diarrhoea by oral B-subunit/whole-cell cholera vaccine. Lancet 1991; 338: 1285–89. Isidean SD, Riddle MS, Savarino SJ, Porter CK. A systematic review of ETEC epidemiology focusing on colonization factor and toxin expression. Vaccine 2011; 29: 6167–78. McKenzie R, Bourgeois AL, Frech SA, et al. Transcutaneous immunization with the heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC): protective efficacy in a double-blind, placebo-controlled challenge study. Vaccine 2007; 25: 3684–91. Frech SA, Dupont HL, Bourgeois AL, et al. Use of a patch containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial. Lancet 2008; 371: 2019–25. Glenn GM, Francis DH, Danielsen EM. Toxin-mediated effects on the innate mucosal defenses: implications for enteric vaccines. Infect Immun 2009; 77: 5206–15. Steffen R, Cramer JP, Burchard G, et al. Efficacy of a travelers’ diarrhea vaccine system in travelers to India. J Travel Med 2013; 20: 374–79. Fleckenstein JM, Munson GM, Rasko D. Enterotoxigenic Escherichia coli: orchestrated host engagement. Gut Microbes 2013; 4: 392–96. Connor BA, Riddle MS. Post-infectious sequelae of travelers’ diarrhea. J Travel Med 2013; 20: 303–12. Frech S. Use of a patch containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial. 42nd US–Japan Conference on Cholera; Austin, TX, USA; Dec 4–7, 2007.
Decrease in antibiotic use, an added benefit of PCVs Acute respiratory illnesses, especially acute otitis media, are leading causes of antibiotic use in children. However, antibiotic use, either necessary or unnecessary, contributes to the emergence of resistance and is a known risk factor for carriage and spread of resistant bacteria.1 Several initiatives promoting judicious use of antibiotics have been launched and implemented. www.thelancet.com/infection Vol 14 March 2014
Active educational efforts on the consequences of overuse of antibiotics and the need for more accurate diagnosis before prescribing them (especially acute otitis media) have been associated with overall decreases in antibiotic use. However, these reductions have been small, and increases in use of broad spectrum antibiotics, especially macrolides, have been noted. In addition to these necessary educational activities, other interventions
Published Online November 26, 2013 http://dx.doi.org/10.1016/ S1473-3099(13)70356-6 See Articles page 205
175
Comment
James King-Holmes/Science Photo Library
are needed to effectively reduce unnecessary antibiotic use. Arguably, the best strategy to prevent unnecessary prescription of antibiotics in general and of broad spectrum antibiotics particularly is to prevent the disorders that could cause the antibiotic prescription. Pneumococcal conjugate vaccines (PCVs) have led to sustained decreases in the incidence of invasive and noninvasive pneumococcal diseases.2–4 PCVs have also reduced incidence of disease caused by antibiotic-resistant bacteria,5–8 and, through disease prevention, reduced antibiotic use.5,9–11 Nevertheless, reductions in antibiotic prescriptions and antimicrobial-resistance have not been routinely included in cost-effectiveness assessments of PCV vaccination programmes.12 In The Lancet Infectious Diseases, Arto Palmu and colleagues13 describe the effectiveness of vaccination with a ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHID-CV10) in reducing outpatient antibiotic purchases. The investigators did a large, carefully designed, cluster randomised controlled trial in Finland. The trial included groups randomised to three plus one and two plus one vaccination schedules (with their respective controls), and included infants younger than 7 months for the primary vaccination series and older infants and toddlers for catch-up doses. All schedules included a booster dose.14 Follow-up and outcome ascertainment was achieved through review of antibiotic purchases recorded in a national registry. Results from the study showed that vaccination with PHID-CV10 reduced outpatient purchases of antibiotics recommended for management of acute otitis media by 8% relative to the purchases with control vaccines. The assessment of purchases of any antibiotic as a secondary outcome yielded similar results. The estimated effectiveness was almost identical between the three plus one and two plus one schedules. Although the 8% relative reduction might seem small, the absolute burden of antimicrobial use was substantial and the investigators estimated that during the 2 year follow-up, vaccination of five children resulted in prevention of one antibiotic purchase. Outcome data for the trial were ascertained from existing records of antibiotic purchases gathered systematically as part of an existing comprehensive and fully linked data system. This method assured that the outcome data were complete and gathered without regard to intervention information. Nevertheless, the 176
specific reason for antibiotic purchase was known only for about 52% of purchases. Of these with known indications, most were for acute otitis media, but, whether defined diagnostic and treatment criteria were standardised across the study clusters is unknown. One might expect, however, that this potential outcome misclassification would probably favour the null hypothesis, making the presented results conservative estimates of the true vaccination effectiveness. This powerful research strategy of using existing registries has been applied by the study investigators and other groups in the past, but the strategy has only recently generated substantial interest as an attractive model and innovative alternative to the follow-up of traditional randomised controlled trials.15 Findings from this trial provide new evidence on the effectiveness of PHID-CV10 in decreasing antibiotic use, and show the effectiveness of the two plus one schedule in this regard. These findings add substantially to the growing body of evidence supporting the benefits of the shortened two plus one schedule.14 This vaccination schedule is currently used in several countries with reported effectiveness in the prevention of disease outcomes very similar to those from countries using three plus one schedule. The cost-effectiveness of switching from a three plus one to a two plus one vaccination schedule is undergoing detailed assessment.16 Despite the encouraging findings of the trial,13 vaccination with PCVs is only a first step in the reduction of antibiotic resistance. Effective campaigns to promote the judicious use of antibiotics, including antibiotic stewardship programmes, are needed to support the added, yet sometimes underappreciated, benefit of PCVs in terms of reduction of antibiotic consumption. Carlos G Grijalva Department of Health Policy, Vanderbilt University School of Medicine, 1500 21st Avenue South, The Village at Vanderbilt Suite 2600, Nashville, TN 37212, USA [email protected] CGG has received research support from the US Centers for Disease Control and Prevention, the Thrasher Research Fund, and Pfizer; he has served as consultant for Pfizer and GlaxoSmithKline. 1
2
3
Schrag SJ, Beall B, Dowell SF. Limiting the spread of resistant pneumococci: biological and epidemiologic evidence for the effectiveness of alternative interventions. Clin Microbiol Rev 2000; 13: 588–601. Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis 2010; 201: 32–41. Griffin MR, Zhu Y, Moore MR, Whitney CG, Grijalva CG. U.S. Hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med 2013; 369: 155–63.
www.thelancet.com/infection Vol 14 March 2014
Comment
4
5 6
7
8
9
10
Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet 2007; 369: 1179–86. Dagan R, Klugman KP. Impact of conjugate pneumococcal vaccines on antibiotic resistance. Lancet Infect Dis 2008; 8: 785–95. Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003; 349: 1341–48. Kyaw MH, Lynfield R, Schaffner W, et al. Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae. N Engl J Med 2006; 354: 1455–63. Hampton LM, Farley MM, Schaffner W, et al. Prevention of antibiotic-nonsusceptible Streptococcus pneumoniae with conjugate vaccines. J Infect Dis 2012; 205: 401–11. Fireman B, Black SB, Shinefield HR, Lee J, Lewis E, Ray P. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J 2003; 22: 10–16. Dagan R, Sikuler-Cohen M, Zamir O, Janco J, Givon-Lavi N, Fraser D. Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day-care center attendees. Pediatr Infect Dis J 2001; 20: 951–58.
11 12
13
14
15 16
Wilby KJ, Werry D. A review of the effect of immunization programs on antimicrobial utilization. Vaccine 2012; 30: 6509–14. Beutels P, Thiry N, Van Damme P. Convincing or confusing? Economic evaluations of childhood pneumococcal conjugate vaccination—a review (2002–2006). Vaccine 2007; 25: 1355–67. Palmu AA, Jokinen J, Nieminen H, et al. Effect of pneumococcal Haemophilus Influenzae protein D conjugate vaccine (PHiD-C) on outpatient antimicrobial purchases: a double-blind, cluster randomised phase 3–4 trial. Lancet Infect Dis 2013; published online Nov 26. http://dx.doi.org/10.1016/S14733099(13)70338-4. Palmu AA, Jokinen J, Borys D, et al. Effectiveness of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against invasive pneumococcal disease: a cluster randomised trial. Lancet 2013; 381: 214–22. Lauer MS, D’Agostino RB Sr. The randomized registry trial—the next disruptive technology in clinical research? N Engl J Med 2013; 369: 1579–81. Stoecker C, Hampton LM, Link-Gelles R, Messonnier ML, Zhou F, Moore MR. Cost-effectiveness of using 2 vs 3 primary doses of 13-valent pneumococcal conjugate vaccine. Pediatrics 2013; 132: e324–32.
Antibiotic prescription for sore throat or the legacy of Mr X² In his 1945 Nobel lecture, Sir Alexander Fleming described a hypothetical “Mr. X, [who] has a sore throat...buys some penicillin and gives himself, not enough to kill the streptococci but enough to educate them to resist penicillin”.1 Ironically, this eminent scientist selected group A streptococci for his example— the leading cause of bacterial pharyngitis and almost the sole organism that remains universally susceptible to penicillin in an era of multidrug-resistant bacteria.2 However, more generally, Fleming was prescient; antibiotic misuse drives antimicrobial resistance and pharyngitis—mainly caused by respiratory viruses—is a cornerstone of antibiotic overuse in the community. Findings of a recent analysis3 of US outpatient data between 1997 and 2010 showed that antibiotics— often macrolides instead of penicillins—were prescribed to 60% of patients who visited the clinic or emergency department because of sore throat. Although most guidelines concur that penicillins should be first-line in the antibiotic treatment, marked heterogeneity exists as to when that treatment should be deployed to prevent complications.4–6 For a complaint as common as sore throat, the scarcity of observational data for the occurrence of complications in patients treated with or without antibiotics is therefore surprising. In this issue, Paul Little and colleagues7 partly fill this knowledge gap by reporting the results of DESCARTE, a pragmatic observational cohort study analysing the effect of three different antibiotic-prescribing strategies www.thelancet.com/infection Vol 14 March 2014
(no antibiotics, delayed antibiotics, and immediate antibiotics) on suppurative complications in nearly 13 000 adult patients with pharyngitis consulting general practices in England and Wales between 2006 and 2009. 1·4% of patients had complications (mostly otitis media or sinusitis). After adjusting for potential confounders, antibiotic prescription (both immediate and delayed) was associated with fewer complications and reconsultations than no antibiotic prescription. This prospective study is remarkable for its size; a recently updated Cochrane review8 on the same topic yielded roughly the same total number of patients after including 27 randomised controlled trials (RCTs) and quasi-RCTs, many of them done in the 1950s. Another strength of this study is the thorough statistical analysis, which confirmed that the estimated effects of antibiotic prescription were robust using different models. How should one interpret the findings of this study? First, findings confirm that, independent of antibiotic prescription, pharyngitis complications are rare and mostly minor, important information for risk-adverse physicians and patients (a separately published analysis9 also showed that these complications are difficult to predict). Although antibiotics (both immediate and delayed) reduced suppurative complications, the recorded reduction in risk was lower than in the Cochrane review.8 In the present study, the estimated number needed to treat to prevent one complication was 193 for immediate and 174 for delayed antibiotics.
Published Online January 17 2013 http://dx.doi.org/10.1016/ S1473-3099(13)70694-7 See Articles page 213
177
protection against diarrhoea associated with ST-only ETEC or all-cause diarrhoea was seen. Supplemented by Behrens and colleagues’ findings,1 the weight of evidence suggests the need to include other antigens in addition to an LT-based component to achieve enough protection against ETEC diarrhoea to have a positive effect on public health. Our understanding of ETEC pathogenesis continues to develop, and novel target antigens have been identified and need to be fully assessed in relevant animal models and moved rapidly to the field for testing.10 We encourage Behrens and colleagues to present more complete data from this trial. For example, more might be learned from advanced cellular and humoral immunological study of available samples to identify a correlate of protection. Furthermore, the potential of an ETEC vaccine to prevent both the acute disease and the chronic consequences such as postinfectious irritable bowel syndrome, which some studies have shown to be associated with travellers’ diarrhoea,11 has yet to be fully appreciated from the phase 3 data. A preliminary positive signal was noted from the phase 2 LT-patch study,12 when at the 6 month follow-up none of the eight assessable participants in the LT-vaccine group who had diarrhoea developed incident irritable bowel syndrome, whereas three of 17 participants in the placebo group did develop the disorder (although this difference was nonsignificant). If such an association were to hold true in the phase 3 results, the potential value of an ETEC vaccine in a traveller target population could rise substantially. We believe that the future of ETEC vaccine research has brightened with coalescence of a broad interest across the global health community, industry, and academia. The synergy between these partners will hopefully continue to push basic and applied research forward, and
advance vaccine candidates expeditiously through clinical assessment. *Mark S Riddle, Stephen J Savarino Naval Medical Research Center, Silver Spring, MD 20910, USA [email protected] We declare that we have no conflicts of interest. Both authors are employees of the US Government or military service members. The views expressed are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government. Copyright protection is not available for any work of the US Government. 1
2
3
4 5
6
7
8
9 10 11 12
Behrens RH, Cramer JP, Jelinek T, et al. Efficacy and safety of a patch vaccine containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala. Lancet Infect Dis 2013; published online Nov 29. http://dx.doi.org/10.1016/S1473-3099(13)70355-4. PATH, BIO Ventures for Global Health. The case for investment in enterotoxigenic Escherichia coli vaccines. PATH, BIO Ventures for Global Health, 2011. http://www.path.org/publications/files/VAC-etec-investmentrpt.pdf (accessed Nov 6, 2013). Clemens JD, Sack DA, Harris JR, et al. Cross-protection by B subunit-whole cell cholera vaccine against diarrhea associated with heat-labile toxin-producing enterotoxigenic Escherichia coli: results of a large-scale field trial. J Infect Dis 1988; 158: 372–77. Peltola H, Siitonen A, Kyrönseppä H, et al. Prevention of travellers’ diarrhoea by oral B-subunit/whole-cell cholera vaccine. Lancet 1991; 338: 1285–89. Isidean SD, Riddle MS, Savarino SJ, Porter CK. A systematic review of ETEC epidemiology focusing on colonization factor and toxin expression. Vaccine 2011; 29: 6167–78. McKenzie R, Bourgeois AL, Frech SA, et al. Transcutaneous immunization with the heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC): protective efficacy in a double-blind, placebo-controlled challenge study. Vaccine 2007; 25: 3684–91. Frech SA, Dupont HL, Bourgeois AL, et al. Use of a patch containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial. Lancet 2008; 371: 2019–25. Glenn GM, Francis DH, Danielsen EM. Toxin-mediated effects on the innate mucosal defenses: implications for enteric vaccines. Infect Immun 2009; 77: 5206–15. Steffen R, Cramer JP, Burchard G, et al. Efficacy of a travelers’ diarrhea vaccine system in travelers to India. J Travel Med 2013; 20: 374–79. Fleckenstein JM, Munson GM, Rasko D. Enterotoxigenic Escherichia coli: orchestrated host engagement. Gut Microbes 2013; 4: 392–96. Connor BA, Riddle MS. Post-infectious sequelae of travelers’ diarrhea. J Travel Med 2013; 20: 303–12. Frech S. Use of a patch containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial. 42nd US–Japan Conference on Cholera; Austin, TX, USA; Dec 4–7, 2007.
Decrease in antibiotic use, an added benefit of PCVs Acute respiratory illnesses, especially acute otitis media, are leading causes of antibiotic use in children. However, antibiotic use, either necessary or unnecessary, contributes to the emergence of resistance and is a known risk factor for carriage and spread of resistant bacteria.1 Several initiatives promoting judicious use of antibiotics have been launched and implemented. www.thelancet.com/infection Vol 14 March 2014
Active educational efforts on the consequences of overuse of antibiotics and the need for more accurate diagnosis before prescribing them (especially acute otitis media) have been associated with overall decreases in antibiotic use. However, these reductions have been small, and increases in use of broad spectrum antibiotics, especially macrolides, have been noted. In addition to these necessary educational activities, other interventions
Published Online November 26, 2013 http://dx.doi.org/10.1016/ S1473-3099(13)70356-6 See Articles page 205
175
Comment
James King-Holmes/Science Photo Library
are needed to effectively reduce unnecessary antibiotic use. Arguably, the best strategy to prevent unnecessary prescription of antibiotics in general and of broad spectrum antibiotics particularly is to prevent the disorders that could cause the antibiotic prescription. Pneumococcal conjugate vaccines (PCVs) have led to sustained decreases in the incidence of invasive and noninvasive pneumococcal diseases.2–4 PCVs have also reduced incidence of disease caused by antibiotic-resistant bacteria,5–8 and, through disease prevention, reduced antibiotic use.5,9–11 Nevertheless, reductions in antibiotic prescriptions and antimicrobial-resistance have not been routinely included in cost-effectiveness assessments of PCV vaccination programmes.12 In The Lancet Infectious Diseases, Arto Palmu and colleagues13 describe the effectiveness of vaccination with a ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHID-CV10) in reducing outpatient antibiotic purchases. The investigators did a large, carefully designed, cluster randomised controlled trial in Finland. The trial included groups randomised to three plus one and two plus one vaccination schedules (with their respective controls), and included infants younger than 7 months for the primary vaccination series and older infants and toddlers for catch-up doses. All schedules included a booster dose.14 Follow-up and outcome ascertainment was achieved through review of antibiotic purchases recorded in a national registry. Results from the study showed that vaccination with PHID-CV10 reduced outpatient purchases of antibiotics recommended for management of acute otitis media by 8% relative to the purchases with control vaccines. The assessment of purchases of any antibiotic as a secondary outcome yielded similar results. The estimated effectiveness was almost identical between the three plus one and two plus one schedules. Although the 8% relative reduction might seem small, the absolute burden of antimicrobial use was substantial and the investigators estimated that during the 2 year follow-up, vaccination of five children resulted in prevention of one antibiotic purchase. Outcome data for the trial were ascertained from existing records of antibiotic purchases gathered systematically as part of an existing comprehensive and fully linked data system. This method assured that the outcome data were complete and gathered without regard to intervention information. Nevertheless, the 176
specific reason for antibiotic purchase was known only for about 52% of purchases. Of these with known indications, most were for acute otitis media, but, whether defined diagnostic and treatment criteria were standardised across the study clusters is unknown. One might expect, however, that this potential outcome misclassification would probably favour the null hypothesis, making the presented results conservative estimates of the true vaccination effectiveness. This powerful research strategy of using existing registries has been applied by the study investigators and other groups in the past, but the strategy has only recently generated substantial interest as an attractive model and innovative alternative to the follow-up of traditional randomised controlled trials.15 Findings from this trial provide new evidence on the effectiveness of PHID-CV10 in decreasing antibiotic use, and show the effectiveness of the two plus one schedule in this regard. These findings add substantially to the growing body of evidence supporting the benefits of the shortened two plus one schedule.14 This vaccination schedule is currently used in several countries with reported effectiveness in the prevention of disease outcomes very similar to those from countries using three plus one schedule. The cost-effectiveness of switching from a three plus one to a two plus one vaccination schedule is undergoing detailed assessment.16 Despite the encouraging findings of the trial,13 vaccination with PCVs is only a first step in the reduction of antibiotic resistance. Effective campaigns to promote the judicious use of antibiotics, including antibiotic stewardship programmes, are needed to support the added, yet sometimes underappreciated, benefit of PCVs in terms of reduction of antibiotic consumption. Carlos G Grijalva Department of Health Policy, Vanderbilt University School of Medicine, 1500 21st Avenue South, The Village at Vanderbilt Suite 2600, Nashville, TN 37212, USA [email protected] CGG has received research support from the US Centers for Disease Control and Prevention, the Thrasher Research Fund, and Pfizer; he has served as consultant for Pfizer and GlaxoSmithKline. 1
2
3
Schrag SJ, Beall B, Dowell SF. Limiting the spread of resistant pneumococci: biological and epidemiologic evidence for the effectiveness of alternative interventions. Clin Microbiol Rev 2000; 13: 588–601. Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis 2010; 201: 32–41. Griffin MR, Zhu Y, Moore MR, Whitney CG, Grijalva CG. U.S. Hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med 2013; 369: 155–63.
www.thelancet.com/infection Vol 14 March 2014
Comment
4
5 6
7
8
9
10
Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet 2007; 369: 1179–86. Dagan R, Klugman KP. Impact of conjugate pneumococcal vaccines on antibiotic resistance. Lancet Infect Dis 2008; 8: 785–95. Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003; 349: 1341–48. Kyaw MH, Lynfield R, Schaffner W, et al. Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae. N Engl J Med 2006; 354: 1455–63. Hampton LM, Farley MM, Schaffner W, et al. Prevention of antibiotic-nonsusceptible Streptococcus pneumoniae with conjugate vaccines. J Infect Dis 2012; 205: 401–11. Fireman B, Black SB, Shinefield HR, Lee J, Lewis E, Ray P. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J 2003; 22: 10–16. Dagan R, Sikuler-Cohen M, Zamir O, Janco J, Givon-Lavi N, Fraser D. Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day-care center attendees. Pediatr Infect Dis J 2001; 20: 951–58.
11 12
13
14
15 16
Wilby KJ, Werry D. A review of the effect of immunization programs on antimicrobial utilization. Vaccine 2012; 30: 6509–14. Beutels P, Thiry N, Van Damme P. Convincing or confusing? Economic evaluations of childhood pneumococcal conjugate vaccination—a review (2002–2006). Vaccine 2007; 25: 1355–67. Palmu AA, Jokinen J, Nieminen H, et al. Effect of pneumococcal Haemophilus Influenzae protein D conjugate vaccine (PHiD-C) on outpatient antimicrobial purchases: a double-blind, cluster randomised phase 3–4 trial. Lancet Infect Dis 2013; published online Nov 26. http://dx.doi.org/10.1016/S14733099(13)70338-4. Palmu AA, Jokinen J, Borys D, et al. Effectiveness of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against invasive pneumococcal disease: a cluster randomised trial. Lancet 2013; 381: 214–22. Lauer MS, D’Agostino RB Sr. The randomized registry trial—the next disruptive technology in clinical research? N Engl J Med 2013; 369: 1579–81. Stoecker C, Hampton LM, Link-Gelles R, Messonnier ML, Zhou F, Moore MR. Cost-effectiveness of using 2 vs 3 primary doses of 13-valent pneumococcal conjugate vaccine. Pediatrics 2013; 132: e324–32.
Antibiotic prescription for sore throat or the legacy of Mr X² In his 1945 Nobel lecture, Sir Alexander Fleming described a hypothetical “Mr. X, [who] has a sore throat...buys some penicillin and gives himself, not enough to kill the streptococci but enough to educate them to resist penicillin”.1 Ironically, this eminent scientist selected group A streptococci for his example— the leading cause of bacterial pharyngitis and almost the sole organism that remains universally susceptible to penicillin in an era of multidrug-resistant bacteria.2 However, more generally, Fleming was prescient; antibiotic misuse drives antimicrobial resistance and pharyngitis—mainly caused by respiratory viruses—is a cornerstone of antibiotic overuse in the community. Findings of a recent analysis3 of US outpatient data between 1997 and 2010 showed that antibiotics— often macrolides instead of penicillins—were prescribed to 60% of patients who visited the clinic or emergency department because of sore throat. Although most guidelines concur that penicillins should be first-line in the antibiotic treatment, marked heterogeneity exists as to when that treatment should be deployed to prevent complications.4–6 For a complaint as common as sore throat, the scarcity of observational data for the occurrence of complications in patients treated with or without antibiotics is therefore surprising. In this issue, Paul Little and colleagues7 partly fill this knowledge gap by reporting the results of DESCARTE, a pragmatic observational cohort study analysing the effect of three different antibiotic-prescribing strategies www.thelancet.com/infection Vol 14 March 2014
(no antibiotics, delayed antibiotics, and immediate antibiotics) on suppurative complications in nearly 13 000 adult patients with pharyngitis consulting general practices in England and Wales between 2006 and 2009. 1·4% of patients had complications (mostly otitis media or sinusitis). After adjusting for potential confounders, antibiotic prescription (both immediate and delayed) was associated with fewer complications and reconsultations than no antibiotic prescription. This prospective study is remarkable for its size; a recently updated Cochrane review8 on the same topic yielded roughly the same total number of patients after including 27 randomised controlled trials (RCTs) and quasi-RCTs, many of them done in the 1950s. Another strength of this study is the thorough statistical analysis, which confirmed that the estimated effects of antibiotic prescription were robust using different models. How should one interpret the findings of this study? First, findings confirm that, independent of antibiotic prescription, pharyngitis complications are rare and mostly minor, important information for risk-adverse physicians and patients (a separately published analysis9 also showed that these complications are difficult to predict). Although antibiotics (both immediate and delayed) reduced suppurative complications, the recorded reduction in risk was lower than in the Cochrane review.8 In the present study, the estimated number needed to treat to prevent one complication was 193 for immediate and 174 for delayed antibiotics.
Published Online January 17 2013 http://dx.doi.org/10.1016/ S1473-3099(13)70694-7 See Articles page 213
177
