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Time to reconsider how we do antibiotic therapy trials
Comment
Time to reconsider how we do antibiotic therapy trials Published Online December 22, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)71063-1 See Articles page 161
132
Community-acquired pneumonia is the leading cause of hospital admissions for infectious disease in Europe, and a major cause of morbidity and mortality. According to the results of Global Burden of Disease study,1 in the WHO European region, community-acquired pneumonia accounted for 230 000 (2·3%) deaths and 2·2 million (1·5%) disability-adjusted life-years in 2010 and was ranked the fifth most common cause of death in the continent.1 The incidence of communityacquired pneumonia increases with age and the burden is therefore set to become greater and more costly with the ageing worldwide population. Despite much progress in medicine, and in critical care particularly, short-term mortality of patients admitted to hospital with community-acquired pneumonia remains high—between 10 and 20%.2 However, unlike nosocomial infections, development of resistance to antimicrobials in the most important pathogens that cause community-acquired pneumonia does not have a role in maintaining this high mortality. Although health care-associated pneumonia caused by multidrugresistant pathogens has been described as a special form of community-acquired pneumonia in the guidelines of the American Thoracic Society,3 an effect of multidrugresistance on the outcome of community-acquired pneumonia has not been confirmed.4 Other risk factors such as age, disability, and chronic comorbidities have a much greater effect on outcome than does the causal pathogen. Unsurprisingly, new antibiotics with additional activity against methicillin-resistant Staphylococcus aureus (MRSA) do not produce better results than older antibiotics in general. Against this background, the results of the phase 3 study reported by Nan Shan Zhong and colleagues5 in The Lancet Infectious Diseases, in which ceftaroline fosamil, a fifth-generation cephalosporin with effectiveness against MRSA, was compared with ceftriaxone in patients admitted to hospital with moderate to severe (Pneumonia Outcomes Research Team [PORT] class III–IV) community-acquired pneumonia in several Asian countries, are very surprising. For the primary endpoint of the study, clinical cure at the test-of-cure visit (8–15 days after last dose of study drug) in the clinically evaluable population, ceftaroline fosamil had a significant advantage over ceftriaxone (217 (84%)
of 258 patients vs 178 (74%) of 240; difference 9·9%, 95% CI 2·8–17·1). Superiority of ceftaroline fosamil was seen consistently for most of the secondary endpoints and most of the subgroups analysed. No differences were identified between treatment groups with respect to adverse events. These findings confirm the results of the approval studies for ceftaroline fosamil, in which it was compared with ceftriaxone in two identical non-inferiority trials.6,7 Both studies confirmed the non-inferiority of ceftaroline fosamil, as expected. Furthermore, pooled data from both studies showed numerically higher proportions of patients cured with ceftaroline fosamil than with ceftriaxone.8 However, the dose of 1 g daily for ceftriaxone used in these studies, which is recommended in the USA, but not in Europe (where 2 g daily is recommended), has been criticised as being too low. Thus Zhong and colleagues5 used a dose of 2 g ceftriaxone in their study and showed the superiority of ceftaroline fosamil 600 mg twice daily. Concentration at the site of infection is essential for the efficacy of an antibiotic. Since lung tissue concentrations are difficult to measure, we normally use serum concentrations to calculate appropriate doses, knowing that they provide only an incomplete picture. In Zhong and colleagues’ study, ceftaroline fosamil was especially more effective than ceftriaxone for Staphylococcus aureus and Gram-negative infections, pathogens for which the minimal inhibitory concentration for ceftaroline fosamil is significantly lower than for ceftriaxone. Two other facts could be of importance with respect to the tissue concentration of these two drugs. About 20% of ceftaroline fosamil binds to plasma protein, compared with 95% of ceftriaxone. Plasma protein binding is an important factor that can affect the tissue penetration of drugs. Additionally, patients given ceftaroline fosamil in this study received a 1 h infusion, whereas those in the ceftriaxone group had a 30 min infusion. Prolonged infusion might have contributed to a higher tissue concentration of ceftaroline fosamil over time. Another explanation for the superiority of ceftaroline fosamil over ceftriaxone could be its better bactericidal activity and faster treatment response. In a post-hoc analysis of the ceftaroline fosamil approval studies www.thelancet.com/infection Vol 15 February 2015
Comment
(required by the US Food and Drug Administration),9 a better clinical response at day 4 was shown with ceftaroline fosamil (70%) than with ceftriaxone (60%) in the pooled analysis. This finding is in line with older data from studies in which moxifloxacin and ceftriaxone were compared,10 which also showed a slower clinical response with ceftriaxone. However, higher bactericidal activity and faster clinical response might be more important in critically ill patients than in those with less severe disease. In Zhong and colleagues’ study, bacteraemia was seen in only slightly more than 1% of patients and the overall mortality was about 1%, which is far less than what is known for patients admitted to hospital with community-acquired pneumonia in observational studies.2 Two main conclusions can be drawn from these results. First, pharmacokinetic findings must be considered and taken more seriously than they are at present. Dose finding is still based on measurement in healthy volunteers, even though serum and tissue concentrations can become lower as patients get more severely ill. Pharmacokinetic studies in patients generally and in critically ill patients especially have to become part of the approval requirements for antibiotics. Second, these results emphasise another weakness of the existing approval process for antibiotics. Only moderately to severely ill (PORT class III–IV) patients were included in Zhong and colleagues’ study, as well as in the pivotal FOCUS studies.6,7 Such patient selection means that benefits of new antibiotics compared with older ones can be shown for measures such as clinical cure, but not for health-care relevant outcomes such as length of hospital stay or mortality. However, data for severe (PORT class V) community-acquired pneumonia are missing for almost all antibiotics. If we want to bring about a change in the high mortality
caused by pneumonia, we have to start to focus more on severe disease and must investigate antibiotics for this indication instead of testing them in patients who will survive anyway, irrespective of the type of antibiotic used. Tobias Welte Deptartment of Pulmonay Medicine, Hannover Medical School, 30625 Hannover, Germany [email protected] I am a member of advisory boards for AstraZeneca, Bayer, Basilea, Cubist, Novartis, and Pfizer. I have received fees for lectures from Bayer, Basilea, Infectopharm, Novartis, and Pfizer 1 2
3
4
5
6
7
8
9
10
Singanayagam A, Chalmers JD, Welte T. Epidemiology of CAP in Europe. Eur Respir Monogr 2014; 63: 1–12. Welte T, Torres A, Nathwani D. Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax 2012; 67: 71–79. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171: 388–416. Chalmers JD, Rother C, Salih W, Ewig S. Healthcare-associated pneumonia does not accurately identify potentially resistant pathogens: a systematic review and meta-analysis. Clin Infect Dis 2014; 58: 330–39. Zhong NS, Sun T, Zhuo C, et al. Ceftaroline fosamil versus ceftriaxone for the treatment of Asian patients with community-acquired pneumonia: a randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial. Lancet Infect Dis; published online Dec 22. http://dx.doi. org/10.1016/S1473-3099(14)71018-7. File TM Jr, Low DE, Eckburg PB, et al. FOCUS 1: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother 2011; 66 (suppl 3): iii19–32. Low DE, File TM Jr, Eckburg PB, et al. FOCUS 2: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother 2011; 66 (suppl 3): iii33–44. File TM Jr, Low DE, Eckburg PB, et al. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia. Clin Infect Dis 2010; 51: 1395–405. Eckburg P, Friedland HD, Llorens L, et al. Day 4 clinical response of ceftaroline fosamil versus ceftriaxone for community-acquired bacterial pneumonia. Infect Dis Clin Pract 2012; 20: 254–60. Welte T, Petermann W, Schürmann D, Bauer TT, Reimnitz P, MOXIRAPID Study Group. Treatment with sequential intravenous or oral moxifloxacin was associated with faster clinical improvement than was standard therapy for hospitalized patients with community-acquired pneumonia who received initial parenteral therapy. Clin Infect Dis 2005; 41: 1697–705.
What we don’t know might hurt us Despite the remarkable successes of immunisation programmes in reducing the global burden of infectious diseases, substantial gaps remain in our basic understanding of vaccine science. Some of these gaps are pathogen-related, such as the identification of protective epitopes, and others are host-related, such as ascertaining the genetic factors associated with www.thelancet.com/infection Vol 15 February 2015
immune responses and susceptibility to adverse events. Knowledge gaps related to vaccine administration also exist. In The Lancet Infectious Diseases, Mildred Iro and colleagues1 sought to address a simple question: for optimum immunogenicity, should sequential doses of infant immunisations be administered in the same limb or in alternating limbs?
Published Online January 8, 2015 http://dx.doi.org/10.1016/ S1473-3099(14)71083-7 See Articles page 172
133
Time to reconsider how we do antibiotic therapy trials Published Online December 22, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)71063-1 See Articles page 161
132
Community-acquired pneumonia is the leading cause of hospital admissions for infectious disease in Europe, and a major cause of morbidity and mortality. According to the results of Global Burden of Disease study,1 in the WHO European region, community-acquired pneumonia accounted for 230 000 (2·3%) deaths and 2·2 million (1·5%) disability-adjusted life-years in 2010 and was ranked the fifth most common cause of death in the continent.1 The incidence of communityacquired pneumonia increases with age and the burden is therefore set to become greater and more costly with the ageing worldwide population. Despite much progress in medicine, and in critical care particularly, short-term mortality of patients admitted to hospital with community-acquired pneumonia remains high—between 10 and 20%.2 However, unlike nosocomial infections, development of resistance to antimicrobials in the most important pathogens that cause community-acquired pneumonia does not have a role in maintaining this high mortality. Although health care-associated pneumonia caused by multidrugresistant pathogens has been described as a special form of community-acquired pneumonia in the guidelines of the American Thoracic Society,3 an effect of multidrugresistance on the outcome of community-acquired pneumonia has not been confirmed.4 Other risk factors such as age, disability, and chronic comorbidities have a much greater effect on outcome than does the causal pathogen. Unsurprisingly, new antibiotics with additional activity against methicillin-resistant Staphylococcus aureus (MRSA) do not produce better results than older antibiotics in general. Against this background, the results of the phase 3 study reported by Nan Shan Zhong and colleagues5 in The Lancet Infectious Diseases, in which ceftaroline fosamil, a fifth-generation cephalosporin with effectiveness against MRSA, was compared with ceftriaxone in patients admitted to hospital with moderate to severe (Pneumonia Outcomes Research Team [PORT] class III–IV) community-acquired pneumonia in several Asian countries, are very surprising. For the primary endpoint of the study, clinical cure at the test-of-cure visit (8–15 days after last dose of study drug) in the clinically evaluable population, ceftaroline fosamil had a significant advantage over ceftriaxone (217 (84%)
of 258 patients vs 178 (74%) of 240; difference 9·9%, 95% CI 2·8–17·1). Superiority of ceftaroline fosamil was seen consistently for most of the secondary endpoints and most of the subgroups analysed. No differences were identified between treatment groups with respect to adverse events. These findings confirm the results of the approval studies for ceftaroline fosamil, in which it was compared with ceftriaxone in two identical non-inferiority trials.6,7 Both studies confirmed the non-inferiority of ceftaroline fosamil, as expected. Furthermore, pooled data from both studies showed numerically higher proportions of patients cured with ceftaroline fosamil than with ceftriaxone.8 However, the dose of 1 g daily for ceftriaxone used in these studies, which is recommended in the USA, but not in Europe (where 2 g daily is recommended), has been criticised as being too low. Thus Zhong and colleagues5 used a dose of 2 g ceftriaxone in their study and showed the superiority of ceftaroline fosamil 600 mg twice daily. Concentration at the site of infection is essential for the efficacy of an antibiotic. Since lung tissue concentrations are difficult to measure, we normally use serum concentrations to calculate appropriate doses, knowing that they provide only an incomplete picture. In Zhong and colleagues’ study, ceftaroline fosamil was especially more effective than ceftriaxone for Staphylococcus aureus and Gram-negative infections, pathogens for which the minimal inhibitory concentration for ceftaroline fosamil is significantly lower than for ceftriaxone. Two other facts could be of importance with respect to the tissue concentration of these two drugs. About 20% of ceftaroline fosamil binds to plasma protein, compared with 95% of ceftriaxone. Plasma protein binding is an important factor that can affect the tissue penetration of drugs. Additionally, patients given ceftaroline fosamil in this study received a 1 h infusion, whereas those in the ceftriaxone group had a 30 min infusion. Prolonged infusion might have contributed to a higher tissue concentration of ceftaroline fosamil over time. Another explanation for the superiority of ceftaroline fosamil over ceftriaxone could be its better bactericidal activity and faster treatment response. In a post-hoc analysis of the ceftaroline fosamil approval studies www.thelancet.com/infection Vol 15 February 2015
Comment
(required by the US Food and Drug Administration),9 a better clinical response at day 4 was shown with ceftaroline fosamil (70%) than with ceftriaxone (60%) in the pooled analysis. This finding is in line with older data from studies in which moxifloxacin and ceftriaxone were compared,10 which also showed a slower clinical response with ceftriaxone. However, higher bactericidal activity and faster clinical response might be more important in critically ill patients than in those with less severe disease. In Zhong and colleagues’ study, bacteraemia was seen in only slightly more than 1% of patients and the overall mortality was about 1%, which is far less than what is known for patients admitted to hospital with community-acquired pneumonia in observational studies.2 Two main conclusions can be drawn from these results. First, pharmacokinetic findings must be considered and taken more seriously than they are at present. Dose finding is still based on measurement in healthy volunteers, even though serum and tissue concentrations can become lower as patients get more severely ill. Pharmacokinetic studies in patients generally and in critically ill patients especially have to become part of the approval requirements for antibiotics. Second, these results emphasise another weakness of the existing approval process for antibiotics. Only moderately to severely ill (PORT class III–IV) patients were included in Zhong and colleagues’ study, as well as in the pivotal FOCUS studies.6,7 Such patient selection means that benefits of new antibiotics compared with older ones can be shown for measures such as clinical cure, but not for health-care relevant outcomes such as length of hospital stay or mortality. However, data for severe (PORT class V) community-acquired pneumonia are missing for almost all antibiotics. If we want to bring about a change in the high mortality
caused by pneumonia, we have to start to focus more on severe disease and must investigate antibiotics for this indication instead of testing them in patients who will survive anyway, irrespective of the type of antibiotic used. Tobias Welte Deptartment of Pulmonay Medicine, Hannover Medical School, 30625 Hannover, Germany [email protected] I am a member of advisory boards for AstraZeneca, Bayer, Basilea, Cubist, Novartis, and Pfizer. I have received fees for lectures from Bayer, Basilea, Infectopharm, Novartis, and Pfizer 1 2
3
4
5
6
7
8
9
10
Singanayagam A, Chalmers JD, Welte T. Epidemiology of CAP in Europe. Eur Respir Monogr 2014; 63: 1–12. Welte T, Torres A, Nathwani D. Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax 2012; 67: 71–79. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171: 388–416. Chalmers JD, Rother C, Salih W, Ewig S. Healthcare-associated pneumonia does not accurately identify potentially resistant pathogens: a systematic review and meta-analysis. Clin Infect Dis 2014; 58: 330–39. Zhong NS, Sun T, Zhuo C, et al. Ceftaroline fosamil versus ceftriaxone for the treatment of Asian patients with community-acquired pneumonia: a randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial. Lancet Infect Dis; published online Dec 22. http://dx.doi. org/10.1016/S1473-3099(14)71018-7. File TM Jr, Low DE, Eckburg PB, et al. FOCUS 1: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother 2011; 66 (suppl 3): iii19–32. Low DE, File TM Jr, Eckburg PB, et al. FOCUS 2: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother 2011; 66 (suppl 3): iii33–44. File TM Jr, Low DE, Eckburg PB, et al. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia. Clin Infect Dis 2010; 51: 1395–405. Eckburg P, Friedland HD, Llorens L, et al. Day 4 clinical response of ceftaroline fosamil versus ceftriaxone for community-acquired bacterial pneumonia. Infect Dis Clin Pract 2012; 20: 254–60. Welte T, Petermann W, Schürmann D, Bauer TT, Reimnitz P, MOXIRAPID Study Group. Treatment with sequential intravenous or oral moxifloxacin was associated with faster clinical improvement than was standard therapy for hospitalized patients with community-acquired pneumonia who received initial parenteral therapy. Clin Infect Dis 2005; 41: 1697–705.
What we don’t know might hurt us Despite the remarkable successes of immunisation programmes in reducing the global burden of infectious diseases, substantial gaps remain in our basic understanding of vaccine science. Some of these gaps are pathogen-related, such as the identification of protective epitopes, and others are host-related, such as ascertaining the genetic factors associated with www.thelancet.com/infection Vol 15 February 2015
immune responses and susceptibility to adverse events. Knowledge gaps related to vaccine administration also exist. In The Lancet Infectious Diseases, Mildred Iro and colleagues1 sought to address a simple question: for optimum immunogenicity, should sequential doses of infant immunisations be administered in the same limb or in alternating limbs?
Published Online January 8, 2015 http://dx.doi.org/10.1016/ S1473-3099(14)71083-7 See Articles page 172
133