- Email: [email protected]
Minimising moxifloxacin resistance with tuberculosis
Reflection and Reaction
Authors’ reply Frederic Frippiat and colleagues question whether we were correct in describing an overall decline in antibiotic use in the community in most developed countries during 1995–2005.1 They base this on data from one paper,2 from which they interpret that the volume of outpatient antibiotic use has increased in “most” European countries between 1997 and 2003. Table 2 from this study2 shows that of the 25 countries for which the authors provided data, 13 did experience an increase in the defined daily dose (DDD) per 1000 inhabitants per day from 1997 to 2003. However, this table also clearly shows a decline in DDD in 12 European countries. Additionally, four of the countries showing a decline (Slovakia, Norway, Israel, and Croatia) had missing data for 3–5 of the 7 years examined. More importantly, we made it clear in our article that we were including developed countries, not just European countries, and cited over 20 studies that support reductions in antibiotic use, including studies from North America.1 Our paper also cited articles using a variety of different measures showing reductions in common respiratory infections, consultations, diagnosis, prescribing rates, and severity of infections. Frippiat and colleagues may have confused the decline in use of antibiotics with the choice of inappropriate antibiotics. In our paper, we discussed the 300% increase in the use of fluoroquinolones in the USA3 to show that even when the overall use of antibiotics is declining, the choice of antibiotic may become less appropriate. We hypothesised that physicians fear that the decline in the overall use of antibiotics has increased the likelihood of complications from respiratory tract infections, so they
choose the most powerful antibiotics when they do elect to prescribe. The two studies that Frippiat and colleagues cite demonstrating increased fluoroquinolone prescribing rely on Belgian data.4,5 Another article they cite shows a decline in antibiotic prescribing (DDD) in Belgium from 25·44 in 1997 to 24·22 in 2003.2 Thus, the data they use to challenge our assertions are actually in line with our argument. Although we described a decline in antibiotic use, our main purpose was to assert that the problem of inappropriate antibiotic prescribing is extremely complex, and far from solved. Because of this, we argued that an ongoing sophisticated research programme is necessary. On this, we and our colleagues appear to be in agreement. *Jarold L Cosby, Nick Francis, Christopher Butler Applied Health Sciences, Brock University, St Catharines, ON, Canada (JLC); Centre for Evaluation of Medicines, McMaster University, Hamilton, ON (JLC); and Department of Primary Care and Public Health, School of Medicine, Cardiff University, Cardiff, UK (JLC, NF, CCB) [email protected] We declare that we have no conflicts of interest. 1
2
3 4
5
Cosby JL, Francis N, Butler CC. The role of evidence in the decline of antibiotic use for common respiratory tract infections in primary care. Lancet Infect Dis 2007; 7: 749–56. Ferech M, Coenen S, Malhotra-Kumar S, et al. European Surveillance of Antimicrobial Consumption (ESAC): outpatient antibiotic use in Europe. J Antimicrobial Chemother 2006; 58: 401–07. Linder JA, Huang ES, Steinman MA, Gonzales R, Stafford RS. Fluroquinolone prescribing in the United States: 1995 to 2002. Am J Med 2005; 118: 259–68. Ferech M, Coenen S, Dvorakova K, et al. European Surveillance of Antimicrobial Consumption (ESAC): outpatient quinolone use in Europe. J Antimicrob Chemother 2006; 58: 423–27. Simoens S, Verhaegen J, Laekman G, Peetermans W. Treating respiratory tract infections in ambulatory care in Belgium: fluroquinolone consumption and resistance development. Int J Antimicrob Agents 2005; 26: 62–68.
Minimising moxifloxacin resistance with tuberculosis
http://infection.thelancet.com Vol 8 May 2008
tuberculosis, defined as MDR tuberculosis plus resistance to a fluoroquinolone and an injectable aminoglycoside. That progression would discourage efforts to develop fluoroquinolones better suited for tuberculosis. We briefly consider tuberculosis surveillance status and then address potential problems with moxifoxacin as an antituberculosis agent. Surveillance studies determine whether resistance is an issue with a given pathogen–antimicrobial pair. When undertaken over many years, surveillance can
CAMR/AB Dowsett/Science Photo Library
Adding the fluoroquinolone moxifloxacin to our armamentarium of antituberculosis agents will be welcomed by many, since Mycobacterium tuberculosis is losing susceptibility to traditional agents. For example, in Lithuania the prevalence of multidrug-resistant (MDR) tuberculosis, defined as resistance to at least rifampicin and isoniazid, has reached 23%.1 Moreover, theoretical modelling by Blower and Supervie2 raised the possibility for exponential progression of MDR tuberculosis to extensively drug-resistant (XDR)
273
Reflection and Reaction
show an initial low prevalence of resistance followed by an almost exponential increase that ends in loss of the clinical indication for a compound.3,4 The challenge is to identify resistance problems before the increase occurs so that therapy can be adjusted to maintain a low prevalence of resistance. In the USA the prevalence of MDR tuberculosis has been dropping slightly: 2% for 1993–99 and 1% for the 2000–06 survey period.5 The fraction of isolates that were XDR tuberculosis held steady at about 0·02%.5 Thus, time may still be available to safeguard moxifloxacin use, provided that global dissemination of XDR tuberculosis is controlled.2 One problem is fluoroquinolone cross-resistance arising from the use of marginally active derivatives, such as ofloxacin and ciprofloxacin. Ofloxacin is used for MDR tuberculosis in many parts of the world; once resistance is acquired to non-quinolone compounds in multidrug treatments, fluoroquinolone resistance is likely to develop (ofloxacin resistance can emerge from 7 days of therapy).6 Moreover, widespread use of fluoroquinolones in general medical practice can create a situation of monotherapy for tuberculosis when the compounds are used for other disease indications, even though patients are actually infected with M tuberculosis.6–8 Particularly problematic is inadvertent treatment of smear-negative pulmonary tuberculosis patients with fluoroquinolones because of misdiagnosis of community-acquired pneumonia:9 previous exposure correlates with fluoroquinolone monoresistance.7 Compounds such as moxifloxacin are lethal enough to M tuberculosis to give a false diagnosis of pneumonia, thereby delaying appropriate treatment for tuberculosis. One or more of the above phenomena may have contributed to the startling finding that 4% of isolates in Baltimore exhibit fluoroquinolone resistance in the absence of resistance to other antituberculosis agents.7 A similar phenomenon is now surfacing in New Jersey (Kreiswirth et al, unpublished data). Since testing for fluoroquinolone monoresistance is not routine, we do not know the full extent of the problem. Moxifloxacin also has pharmacodynamic problems resulting from its long half-life. When compounds are used in a multidrug, combination therapy, an agent with a long half-life can have concentrations above the minimum inhibitory concentration (MIC) when other compounds in the combination have concentrations below MIC. Such situations constitute 274
the equivalent of monotherapy for agents with a long half-life, and resistance can emerge readily.10 The equivalent of monotherapy is expected to occur with moxifloxacin when the dosing interval exceeds 24 h. It will also occur for about half of the daily dosing interval when M tuberculosis is resistant to isoniazid and rifampicin. Thus, future use of moxifloxacin in immunocompromised patients should be monitored carefully for fluoroquinolone monoresistance, as was done with a long half-life derivative of rifampicin.10 In summary, widespread use of fluoroquinolones for other infections and continued use of older fluoroquinolones for tuberculosis will increase the size of fluoroquinolone-resistant M tuberculosis subpopulations, thereby predisposing infection to the emergence of moxifloxacin resistance. Moreover, pharmacodynamic considerations predict that moxifloxacin-resistant mutants will selectively amplify with MDR tuberculosis and with dosing intervals greater than 24 h (for example, when weekend therapy is absent). Combining moxifloxacin and a derivative of rifampicin with a similar half-life into a single tablet could help protect moxifloxacin from the emergence of resistance. Other efforts to preserve moxifloxacin susceptibility include eliminating ofloxacin and ciprofloxacin as treatment for tuberculosis and more widespread use of molecular methods for evaluating individual patients for tuberculosis to reduce cases of misdiagnosis.9 Additionally, molecular methods can be used to evaluate individual patients for quinolone-resistant subpopulations of M tuberculosis to help identify patients carrying such infections. Such methods could result in more cautious treatment and increased sensitivity of surveillance to early stages in the emergence of resistance. *Karl Drlica, Xilin Zhao, Barry Kreiswirth Public Health Research Institute, New Jersey Medical School, University of Medicine and Denistry, New Jersey (UMDNJ), Newark, NJ, USA [email protected] We declare that we have no conflicts of interest. This work was supported by National Institutes of Health grants AI 35257 and AI 73491; the granting agency did not influence the content of the article. 1
2 3
Dewan R, Sosnovskaja A, Thomsen V, et al. High prevalence of drugresistant tuberculosis, Republic of Lithuania, 2002. Int J Tuberc Lung Dis 2005; 9: 170–74. Blower S, Supervie V. Predicting the future of XDR tuberculosis. Lancet Infect Dis 2007; 7: 443. Johnson AP. Antibiotic resistance among clinically important Gram-positive bacteria in the UK. J Hosp Infect 1998; 40: 17–26.
http://infection.thelancet.com Vol 8 May 2008
Reflection and Reaction
4
5 6
7
Baquero F. Trends in antibiotic resistance of respiratory pathogens: an analysis and commentary on a collaborative surveillance study. J Antimicrob Chemother 1996; 38 (suppl A): 117–32. Shah NS, Pratt R, Althomsons S, et al. Extensively drug-resistant tuberculosis— United States, 1993–2006. MMWR Morb Mortal Wkly Rep 2007; 56: 250–53. Wang JY, Hsueh P-R, Jan I, et al. Empirical treatment with a fluoroquinolone delays the treatment for tuberculosis and is associated with a poor prognosis in endemic areas. Thorax 2007; 61: 903–08. Ginsberg A, Hooper N, Parrish N, et al. Fluoroquinolone resistance in newly diagnosed tuberculosis. Clin Infect Dis 2003; 37: 1448–52.
8
9
10
Perlman D, ElSadr W, Heifets L, et al. Susceptibility to levofloxacin of Mycobacterium tuberculosis isolates from patients with HIV-related tuberculosis and characterization of a strain with levofloxacin monoresistance. AIDS 1997; 11: 1473–78. Sterling T. The WHO/IUATLD diagnostic algorithm or tuberculosis and empiric fluoroquinolone use: potential pitfalls. Int J Tuberc Lung Dis 2004; 8: 1396–1400. Vernon A, Burman W, Benator D, Khan A, Bozeman L. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Lancet 1999; 353: 1843–47.
We read the comments of Raymond Tsang1 regarding capsule replacement in vaccine-preventable diseases and challenge the statement that “there is ample evidence of…invasive Haemophilus influenzae disease caused by capsule replacement strains after introduction of…polysaccharide conjugate vaccines”. The European Union Invasive Bacterial Infections Surveillance Network (EU-IBIS) was established in 1999: 29 countries currently provide national surveillance data on invasive H influenzae (defined as isolation of H influenzae from a normally sterile site) and their reference laboratories participate in an external quality assessment scheme run by the Health Protection Agency (HPA), London, UK. Of the 29 countries, 13 (Austria, England and Wales, Finland, Greece, Iceland, Ireland, Italy, Malta, Netherlands, Norway, Portugal, Scotland, and Slovenia) provide comparable data on invasive isolates for all H influenzae serotypes with any clinical diagnosis from all age-groups. All these countries had introduced H influenzae type b (Hib) vaccination into their national infant immunisation programme before this period. Annual incidence rates were calculated using mid-year population estimates.
Between 2000 and 2004, there were 4626 H influenzae cases reported from an average population of 167 million individuals. Of the 3688 (80%) isolates that were serotyped, 38% were Hib, 53% were noncapsulated, and 9% were other encapsulated strains (table). Serotype f accounted for most (74%) of the non-serotype-b encapsulated strains. Although the incidence of Hib increased between 2000 and 2002— mainly as a result of a rise in cases reported in the UK2 and the Netherlands3—before falling in 2003, there was no evidence of an increase in non-b serotypes when analysed by country, age-group, clinical diagnosis, or outcome. The proportion of H influenzae strains that were serotyped has remained fairly stable and there was no change in clinical presentation or case-fatality ratio. In the USA, an analysis of three separate surveillance systems covering a population of 10–13 million people between 1987 and 1995 showed no increase in the incidence of non-serotype-b disease following the introduction of Hib vaccination.4 This finding has been supported by other North American reports.5,6 Mass vaccination has not only lowered the incidence of invasive Hib disease, but has also reduced asymptomatic
Hib
Other capsulated
Non-capsulated
Not known
Total
Total
Serotype a
Serotype c
Serotype d
Serotype e
Serotype f
2000
1·11 (173)
0·31 (49)
0·03 (5)
0·01 (1)
0·01 (2)
0·04 (7)
0·22 (34)
2001
1·34 (210)
0·47 (74)
0·02 (3)
0·00 (0)
0·00 (0)
0·08 (13)
0·37 (58)
2·33 (364)
1·15 (180)
4·90 (766)
2·52 (395)
1·22 (191)
2002
2·27 (376)
0·39 (64)
0·01 (1)
0·01 (1)
0·00 (0)
0·08 (13)
0·30 (49)
5·54 (870)
1·99 (330)
1·55 (257)
6·20 (1027)
2003
2·14 (380)
0·44 (78)
0·00 (0)
0·01 (2)
0·01 (1)
0·11 (20)
2004
1·50 (268)
0·40 (72)
0·01 (2)
0·01 (1)
0·01 (2)
0·08 (15)
0·31 (55)
2·65 (470)
0·88 (156)
6·11 (1084)
0·29 (52)
2·13 (380)
0·89 (159)
Total
1·69 (1407)
0·40 (337)
0·01 (11)
0·01 (5)
0·01 (5)
0·08 (68)
0·30 (248) 2·32 (1939)
4·92 (879)
1·13 (943)
5·54 (4626)
CNRI/Science Photo Library
No evidence for Haemophilus influenzae serotype replacement in Europe after introduction of the Hib conjugate vaccine
For more information on EU-IBIS see http://www.euibis. org
Serotype incidence per million cases (number of cases).
Table: Incidence of invasive H influenzae disease in Europe by serotype in the era of Hib conjugate vaccination (2000–04)
http://infection.thelancet.com Vol 8 May 2008
275
Authors’ reply Frederic Frippiat and colleagues question whether we were correct in describing an overall decline in antibiotic use in the community in most developed countries during 1995–2005.1 They base this on data from one paper,2 from which they interpret that the volume of outpatient antibiotic use has increased in “most” European countries between 1997 and 2003. Table 2 from this study2 shows that of the 25 countries for which the authors provided data, 13 did experience an increase in the defined daily dose (DDD) per 1000 inhabitants per day from 1997 to 2003. However, this table also clearly shows a decline in DDD in 12 European countries. Additionally, four of the countries showing a decline (Slovakia, Norway, Israel, and Croatia) had missing data for 3–5 of the 7 years examined. More importantly, we made it clear in our article that we were including developed countries, not just European countries, and cited over 20 studies that support reductions in antibiotic use, including studies from North America.1 Our paper also cited articles using a variety of different measures showing reductions in common respiratory infections, consultations, diagnosis, prescribing rates, and severity of infections. Frippiat and colleagues may have confused the decline in use of antibiotics with the choice of inappropriate antibiotics. In our paper, we discussed the 300% increase in the use of fluoroquinolones in the USA3 to show that even when the overall use of antibiotics is declining, the choice of antibiotic may become less appropriate. We hypothesised that physicians fear that the decline in the overall use of antibiotics has increased the likelihood of complications from respiratory tract infections, so they
choose the most powerful antibiotics when they do elect to prescribe. The two studies that Frippiat and colleagues cite demonstrating increased fluoroquinolone prescribing rely on Belgian data.4,5 Another article they cite shows a decline in antibiotic prescribing (DDD) in Belgium from 25·44 in 1997 to 24·22 in 2003.2 Thus, the data they use to challenge our assertions are actually in line with our argument. Although we described a decline in antibiotic use, our main purpose was to assert that the problem of inappropriate antibiotic prescribing is extremely complex, and far from solved. Because of this, we argued that an ongoing sophisticated research programme is necessary. On this, we and our colleagues appear to be in agreement. *Jarold L Cosby, Nick Francis, Christopher Butler Applied Health Sciences, Brock University, St Catharines, ON, Canada (JLC); Centre for Evaluation of Medicines, McMaster University, Hamilton, ON (JLC); and Department of Primary Care and Public Health, School of Medicine, Cardiff University, Cardiff, UK (JLC, NF, CCB) [email protected] We declare that we have no conflicts of interest. 1
2
3 4
5
Cosby JL, Francis N, Butler CC. The role of evidence in the decline of antibiotic use for common respiratory tract infections in primary care. Lancet Infect Dis 2007; 7: 749–56. Ferech M, Coenen S, Malhotra-Kumar S, et al. European Surveillance of Antimicrobial Consumption (ESAC): outpatient antibiotic use in Europe. J Antimicrobial Chemother 2006; 58: 401–07. Linder JA, Huang ES, Steinman MA, Gonzales R, Stafford RS. Fluroquinolone prescribing in the United States: 1995 to 2002. Am J Med 2005; 118: 259–68. Ferech M, Coenen S, Dvorakova K, et al. European Surveillance of Antimicrobial Consumption (ESAC): outpatient quinolone use in Europe. J Antimicrob Chemother 2006; 58: 423–27. Simoens S, Verhaegen J, Laekman G, Peetermans W. Treating respiratory tract infections in ambulatory care in Belgium: fluroquinolone consumption and resistance development. Int J Antimicrob Agents 2005; 26: 62–68.
Minimising moxifloxacin resistance with tuberculosis
http://infection.thelancet.com Vol 8 May 2008
tuberculosis, defined as MDR tuberculosis plus resistance to a fluoroquinolone and an injectable aminoglycoside. That progression would discourage efforts to develop fluoroquinolones better suited for tuberculosis. We briefly consider tuberculosis surveillance status and then address potential problems with moxifoxacin as an antituberculosis agent. Surveillance studies determine whether resistance is an issue with a given pathogen–antimicrobial pair. When undertaken over many years, surveillance can
CAMR/AB Dowsett/Science Photo Library
Adding the fluoroquinolone moxifloxacin to our armamentarium of antituberculosis agents will be welcomed by many, since Mycobacterium tuberculosis is losing susceptibility to traditional agents. For example, in Lithuania the prevalence of multidrug-resistant (MDR) tuberculosis, defined as resistance to at least rifampicin and isoniazid, has reached 23%.1 Moreover, theoretical modelling by Blower and Supervie2 raised the possibility for exponential progression of MDR tuberculosis to extensively drug-resistant (XDR)
273
Reflection and Reaction
show an initial low prevalence of resistance followed by an almost exponential increase that ends in loss of the clinical indication for a compound.3,4 The challenge is to identify resistance problems before the increase occurs so that therapy can be adjusted to maintain a low prevalence of resistance. In the USA the prevalence of MDR tuberculosis has been dropping slightly: 2% for 1993–99 and 1% for the 2000–06 survey period.5 The fraction of isolates that were XDR tuberculosis held steady at about 0·02%.5 Thus, time may still be available to safeguard moxifloxacin use, provided that global dissemination of XDR tuberculosis is controlled.2 One problem is fluoroquinolone cross-resistance arising from the use of marginally active derivatives, such as ofloxacin and ciprofloxacin. Ofloxacin is used for MDR tuberculosis in many parts of the world; once resistance is acquired to non-quinolone compounds in multidrug treatments, fluoroquinolone resistance is likely to develop (ofloxacin resistance can emerge from 7 days of therapy).6 Moreover, widespread use of fluoroquinolones in general medical practice can create a situation of monotherapy for tuberculosis when the compounds are used for other disease indications, even though patients are actually infected with M tuberculosis.6–8 Particularly problematic is inadvertent treatment of smear-negative pulmonary tuberculosis patients with fluoroquinolones because of misdiagnosis of community-acquired pneumonia:9 previous exposure correlates with fluoroquinolone monoresistance.7 Compounds such as moxifloxacin are lethal enough to M tuberculosis to give a false diagnosis of pneumonia, thereby delaying appropriate treatment for tuberculosis. One or more of the above phenomena may have contributed to the startling finding that 4% of isolates in Baltimore exhibit fluoroquinolone resistance in the absence of resistance to other antituberculosis agents.7 A similar phenomenon is now surfacing in New Jersey (Kreiswirth et al, unpublished data). Since testing for fluoroquinolone monoresistance is not routine, we do not know the full extent of the problem. Moxifloxacin also has pharmacodynamic problems resulting from its long half-life. When compounds are used in a multidrug, combination therapy, an agent with a long half-life can have concentrations above the minimum inhibitory concentration (MIC) when other compounds in the combination have concentrations below MIC. Such situations constitute 274
the equivalent of monotherapy for agents with a long half-life, and resistance can emerge readily.10 The equivalent of monotherapy is expected to occur with moxifloxacin when the dosing interval exceeds 24 h. It will also occur for about half of the daily dosing interval when M tuberculosis is resistant to isoniazid and rifampicin. Thus, future use of moxifloxacin in immunocompromised patients should be monitored carefully for fluoroquinolone monoresistance, as was done with a long half-life derivative of rifampicin.10 In summary, widespread use of fluoroquinolones for other infections and continued use of older fluoroquinolones for tuberculosis will increase the size of fluoroquinolone-resistant M tuberculosis subpopulations, thereby predisposing infection to the emergence of moxifloxacin resistance. Moreover, pharmacodynamic considerations predict that moxifloxacin-resistant mutants will selectively amplify with MDR tuberculosis and with dosing intervals greater than 24 h (for example, when weekend therapy is absent). Combining moxifloxacin and a derivative of rifampicin with a similar half-life into a single tablet could help protect moxifloxacin from the emergence of resistance. Other efforts to preserve moxifloxacin susceptibility include eliminating ofloxacin and ciprofloxacin as treatment for tuberculosis and more widespread use of molecular methods for evaluating individual patients for tuberculosis to reduce cases of misdiagnosis.9 Additionally, molecular methods can be used to evaluate individual patients for quinolone-resistant subpopulations of M tuberculosis to help identify patients carrying such infections. Such methods could result in more cautious treatment and increased sensitivity of surveillance to early stages in the emergence of resistance. *Karl Drlica, Xilin Zhao, Barry Kreiswirth Public Health Research Institute, New Jersey Medical School, University of Medicine and Denistry, New Jersey (UMDNJ), Newark, NJ, USA [email protected] We declare that we have no conflicts of interest. This work was supported by National Institutes of Health grants AI 35257 and AI 73491; the granting agency did not influence the content of the article. 1
2 3
Dewan R, Sosnovskaja A, Thomsen V, et al. High prevalence of drugresistant tuberculosis, Republic of Lithuania, 2002. Int J Tuberc Lung Dis 2005; 9: 170–74. Blower S, Supervie V. Predicting the future of XDR tuberculosis. Lancet Infect Dis 2007; 7: 443. Johnson AP. Antibiotic resistance among clinically important Gram-positive bacteria in the UK. J Hosp Infect 1998; 40: 17–26.
http://infection.thelancet.com Vol 8 May 2008
Reflection and Reaction
4
5 6
7
Baquero F. Trends in antibiotic resistance of respiratory pathogens: an analysis and commentary on a collaborative surveillance study. J Antimicrob Chemother 1996; 38 (suppl A): 117–32. Shah NS, Pratt R, Althomsons S, et al. Extensively drug-resistant tuberculosis— United States, 1993–2006. MMWR Morb Mortal Wkly Rep 2007; 56: 250–53. Wang JY, Hsueh P-R, Jan I, et al. Empirical treatment with a fluoroquinolone delays the treatment for tuberculosis and is associated with a poor prognosis in endemic areas. Thorax 2007; 61: 903–08. Ginsberg A, Hooper N, Parrish N, et al. Fluoroquinolone resistance in newly diagnosed tuberculosis. Clin Infect Dis 2003; 37: 1448–52.
8
9
10
Perlman D, ElSadr W, Heifets L, et al. Susceptibility to levofloxacin of Mycobacterium tuberculosis isolates from patients with HIV-related tuberculosis and characterization of a strain with levofloxacin monoresistance. AIDS 1997; 11: 1473–78. Sterling T. The WHO/IUATLD diagnostic algorithm or tuberculosis and empiric fluoroquinolone use: potential pitfalls. Int J Tuberc Lung Dis 2004; 8: 1396–1400. Vernon A, Burman W, Benator D, Khan A, Bozeman L. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Lancet 1999; 353: 1843–47.
We read the comments of Raymond Tsang1 regarding capsule replacement in vaccine-preventable diseases and challenge the statement that “there is ample evidence of…invasive Haemophilus influenzae disease caused by capsule replacement strains after introduction of…polysaccharide conjugate vaccines”. The European Union Invasive Bacterial Infections Surveillance Network (EU-IBIS) was established in 1999: 29 countries currently provide national surveillance data on invasive H influenzae (defined as isolation of H influenzae from a normally sterile site) and their reference laboratories participate in an external quality assessment scheme run by the Health Protection Agency (HPA), London, UK. Of the 29 countries, 13 (Austria, England and Wales, Finland, Greece, Iceland, Ireland, Italy, Malta, Netherlands, Norway, Portugal, Scotland, and Slovenia) provide comparable data on invasive isolates for all H influenzae serotypes with any clinical diagnosis from all age-groups. All these countries had introduced H influenzae type b (Hib) vaccination into their national infant immunisation programme before this period. Annual incidence rates were calculated using mid-year population estimates.
Between 2000 and 2004, there were 4626 H influenzae cases reported from an average population of 167 million individuals. Of the 3688 (80%) isolates that were serotyped, 38% were Hib, 53% were noncapsulated, and 9% were other encapsulated strains (table). Serotype f accounted for most (74%) of the non-serotype-b encapsulated strains. Although the incidence of Hib increased between 2000 and 2002— mainly as a result of a rise in cases reported in the UK2 and the Netherlands3—before falling in 2003, there was no evidence of an increase in non-b serotypes when analysed by country, age-group, clinical diagnosis, or outcome. The proportion of H influenzae strains that were serotyped has remained fairly stable and there was no change in clinical presentation or case-fatality ratio. In the USA, an analysis of three separate surveillance systems covering a population of 10–13 million people between 1987 and 1995 showed no increase in the incidence of non-serotype-b disease following the introduction of Hib vaccination.4 This finding has been supported by other North American reports.5,6 Mass vaccination has not only lowered the incidence of invasive Hib disease, but has also reduced asymptomatic
Hib
Other capsulated
Non-capsulated
Not known
Total
Total
Serotype a
Serotype c
Serotype d
Serotype e
Serotype f
2000
1·11 (173)
0·31 (49)
0·03 (5)
0·01 (1)
0·01 (2)
0·04 (7)
0·22 (34)
2001
1·34 (210)
0·47 (74)
0·02 (3)
0·00 (0)
0·00 (0)
0·08 (13)
0·37 (58)
2·33 (364)
1·15 (180)
4·90 (766)
2·52 (395)
1·22 (191)
2002
2·27 (376)
0·39 (64)
0·01 (1)
0·01 (1)
0·00 (0)
0·08 (13)
0·30 (49)
5·54 (870)
1·99 (330)
1·55 (257)
6·20 (1027)
2003
2·14 (380)
0·44 (78)
0·00 (0)
0·01 (2)
0·01 (1)
0·11 (20)
2004
1·50 (268)
0·40 (72)
0·01 (2)
0·01 (1)
0·01 (2)
0·08 (15)
0·31 (55)
2·65 (470)
0·88 (156)
6·11 (1084)
0·29 (52)
2·13 (380)
0·89 (159)
Total
1·69 (1407)
0·40 (337)
0·01 (11)
0·01 (5)
0·01 (5)
0·08 (68)
0·30 (248) 2·32 (1939)
4·92 (879)
1·13 (943)
5·54 (4626)
CNRI/Science Photo Library
No evidence for Haemophilus influenzae serotype replacement in Europe after introduction of the Hib conjugate vaccine
For more information on EU-IBIS see http://www.euibis. org
Serotype incidence per million cases (number of cases).
Table: Incidence of invasive H influenzae disease in Europe by serotype in the era of Hib conjugate vaccination (2000–04)
http://infection.thelancet.com Vol 8 May 2008
275