JAC Advance Access originally published online on July 28, 2008
Journal of Antimicrobial Chemotherapy 2008 62(4):776-779; doi:10.1093/jac/dkn274
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Original research |
Changes in antibiotic resistance rates of invasive Haemophilus influenzae isolates in England and Wales over the last 20 years
1 Immunisation Department, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London NW9 5EQ, UK 2 Division of Child Health and Vaccine Institute, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK 3 Haemophilus Reference Unit, Respiratory and Systemic Infection Laboratory, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London NW9 5EQ, UK
* Corresponding author. Tel: +44-208-327-7879; E-mail: Shamez.Ladhani{at}hpa.org.uk
Received 20 March 2008; returned 9 May 2008; revised 4 June 2008; accepted 11 June 2008
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Abstract |
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Objectives: The aim of this study was to determine trends in antibiotic resistance profiles of invasive clinical Haemophilus influenzae isolates over the last 20 years.
Methods: Microbiology laboratories throughout England and Wales regularly submit invasive H. influenzae isolates to the Health Protection Agency for serotyping and antimicrobial susceptibility testing. Antimicrobial resistance was defined using the British Society for Antimicrobial Chemotherapy criteria (http://bsac.org.uk). All H. influenzae isolates from blood and cerebrospinal fluid (CSF) cultures between January 1985 and December 2004 were included.
Results: Over the 20 year study period, 6805 H. influenzae isolates from blood (n = 4932, 72.5%) and CSF (n = 1873, 27.5%) were obtained. Over half the isolates (3736/6805, 54.9%) were identified as Hib, 38.9% (n = 2644) as non-capsulated and 6.2% (n = 425) as other capsulated serotypes. Resistance to ampicillin was highest at 16.2%, followed by trimethoprim (7.7%), tetracycline (1.8%) and chloramphenicol (1.2%). All isolates were susceptible to cefotaxime and only four (0.06%) were resistant to rifampicin. When analysing trends, chloramphenicol and tetracycline resistance rates have remained low since the late 1980s. Ampicillin resistance increased slowly until the mid-1990s and then gradually declined to its lowest rate of 11.6% in 2004. Resistance to trimethoprim initially fell from 10% in 1985 to 1.8% in 1989, but has continued to rise since then to 11.9% in 2004. In a logistic regression model, year of isolate (P < 0.001), non-capsulated H. influenzae (P < 0.001) and younger age (P = 0.004) remained independently associated with trimethoprim resistance.
Conclusions: Rifampicin and cefotaxime remain highly effective against all invasive H. influenzae isolates. Resistance to ampicillin, chloramphenicol and tetracycline has declined over the past 10 years, but trimethoprim resistance continues to increase rapidly. This finding requires further study but may reflect increased use of trimethoprim in the childhood population.
Keywords: Haemophilus influenzae serotype b , trimethoprim , antimicrobial resistance surveillance
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Introduction |
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Haemophilus influenzae can cause life-threatening invasive disease in adults and children, including meningitis, septic shock and epiglottitis.1 Early empirical treatment with effective antibiotics is vital in order to prevent serious complications and death. Ampicillin is no longer recommended because of widespread resistance, and although cephalosporins are highly effective against H. influenzae, there are already concerns regarding their use in empirical treatment because of increasing resistance.2–4 Continued surveillance of antimicrobial susceptibility is important in order to monitor resistance trends and identify emerging resistance early. The objective of this study was to determine changes in antibiotic resistance profiles of invasive clinical H. influenzae isolates between 1985 and 2004, with the aim of identifying long-term trends and recommending appropriate antibiotics for treatment and prophylaxis.
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Methods |
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The Health Protection Agency (HPA) Centre for Infections receives H. influenzae isolates and laboratory reports of invasive H. influenzae infections from nearly 400 hospitals and public health laboratories. Between 1985 and 1990, H. influenzae isolates were submitted on a voluntary basis for identity confirmation, serotyping and antimicrobial susceptibility testing. In September 1990, an enhanced surveillance was initiated in five English regions (East Anglia, Northern, North West, South West and Oxford) and Wales, and extended nationally in 1995 following the rapid decline in Hib incidence resulting from national immunization.5 Between 1992 and 2000, enhanced surveillance was complemented by a national clinical paediatric reporting scheme through the British Paediatric Surveillance Unit.5 All reports of H. influenzae isolated from a sterile site were followed-up by contacting the microbiologist and requesting referral of the isolate to the HPA Haemophilus Reference Unit if this had not been already done. Serotyping was performed using standard slide agglutination and confirmed by PCR-based capsular genotyping.6 Antimicrobial susceptibility testing was carried out using a standard disc sensitivity method according to the British Society for Antimicrobial Chemotherapy (BSAC) guidelines.7 Strains were plated out on Iso-Sensitest agar, supplemented with 5% lysed equine blood and 0.2% NAD solution. The following disc concentrations were used: ampicillin 2 µg, trimethoprim 2.5 µg, chloramphenicol 10 µg, tetracycline 10 µg, cefotaxime 30 µg and rifampicin 2 µg. Strains were tested for β-lactamase activity using Intralactam Strips (Mast Laboratories Ltd). All cases were entered into a single Dataease database, reconciled and de-duplicated regularly and analysed using Stata 9.0 (www.stata.com). Proportions were compared using the
2 test. Risk factors for trimethoprim resistance were assessed using backward stepwise logistic regression. |
Results |
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Of the 6805 blood (n = 4932, 72.5%) and cerebrospinal fluid (CSF) (n = 1873, 27.5%) isolates from patients with invasive H. influenzae infection between 1985 and 2004, 54.9% (n = 3736) were identified as Hib, 6.2% (n = 425) as other capsulated strains and 38.9% (n = 2644) as non-capsulated strains. CSF isolates were mostly Hib (83.0%) followed by non-capsulated (14.0%) and other capsulated serotypes (3.0%), compared with 44.2%, 48.3% and 7.5%, respectively, among blood culture isolates. Half the samples (n = 3398, 49.9%) were from children <16 years, of which 38.9% were from CSF and 76.4% were due to Hib compared with 12.2% and 27.5% in adults, respectively.
Figure 1 depicts the antibiotic resistance rates for invasive clinical H. influenzae isolates between 1985 and 2004. Resistance to ampicillin was most common (16.2%), followed by trimethoprim (7.7%), tetracycline (1.8%) and chloramphenicol (1.2%) (Table 1). All isolates were susceptible to cefotaxime and only four (0.06%) were resistant to rifampicin (two non-capsulated, one Hib and one serotype e). Among ampicillin-resistant isolates, β-lactamase production was detected in 97.5% of the 1047 ampicillin-resistant and none of the 5408 ampicillin-susceptible isolates tested. β-Lactamase-negative, ampicillin-resistant (BLNAR) isolates first appeared in 1991, peaked at 8.5% in 1998 and then remained <5% in subsequent years. BLNAR accounted for 0.7% of the 609 Hib isolates, none of 27 other capsulated and 5.4% of the 411 non-capsulated isolates.
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Comparison of antibiotic resistances between two 10 year time periods (1985–94 and 1995–2004) showed downward trends for ampicillin (427/2488, 17.2%
624/4002, 15.6%; 2 = 2.8; P = 0.095), chloramphenicol (32/2482, 1.3% 44/3985, 1.1%; 2 = 0.45; P = 0.50) and tetracycline (53/2449, 2.2% 62/3978, 1.6%; 2 = 3.16; P = 0.075), although these were not statistically significant. For ampicillin, the decline in resistance rates was statistically significant after 1998 (2 for trend = 16.1, P = 0.013). In contrast, trimethoprim resistance increased 3-fold from 3.6% (88/2468 isolates) to 10.2% (407/3988 isolates, 2 = 94.9, P < 0.0001). This increase occurred in both adult (26/584, 4.5% 224/2337, 9.6%; 2 = 15.7; P < 0.0001) and paediatric (60/1813, 3.3% 172/1543, 11.1%; 2 = 79.6; P < 0.0001) isolates, blood (50/1144, 4.4% 374/3597, 10.4%; 2 = 38.7; P < 0.0001) and CSF (38/1324, 2.9%33/391, 8.4%; 2 = 23.6; P < 0.0001) isolates, and in Hib (57/2037, 2.8% 109/1413, 7.7%; 2 = 44.0; P < 0.0001), other capsulated (0/57, 0.0% 27/346, 7.8%; 2 = 4.8; P = 0.029) and non-capsulated (31/374, 8.3% 271/2229, 12.2%; 2 = 4.7; P = 0.031) strains. In a logistic regression model, the year of isolate (P < 0.001), non-capsulated H. influenzae (P < 0.001) and younger age (P = 0.004), but not the source of isolate (P = 0.22), remained independently associated with trimethoprim resistance.
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Comparison of Hib with non-Hib isolates for three time periods between 1985 and 1992 (pre-vaccination, 1765 versus 209 isolates), 1993 and 1999 (post-vaccination, 644 versus 1294 isolates) and 2000 and 2004 (period of Hib disease resurgence, 1327 versus 1566 isolates) did not reveal any difference in antibiotic resistance trends for ampicillin (17.1%, 20.6%, 16.6% versus 11.0%, 17.1%, 13.1%), tetracycline (2.5%, 3.1%, 1.7% versus 1.5%, 1.3%, 0.9%) or trimethoprim (2.9%, 4.6%, 8.1% versus 5.7%, 9.2%, 13.2%) that might be attributable to the introduction of the Hib conjugate vaccine into the national infant immunization programme.
Resistance to multiple antibiotics was uncommon. Chloramphenicol and tetracycline resistance were strongly correlated—99.2% of the 6339 chloramphenicol-susceptible strains were also tetracycline-susceptible, while 85.5% of the 76 chloramphenicol-resistant strains were also tetracycline-resistant. Combined chloramphenicol and ampicillin resistance occurred in 1.1% of the 6466 isolates and remained <2.0% throughout the 20 years, with no evidence of an increasing trend. Combined resistance to these two antibiotics was found in 1.4% (47/3461) of Hib, 0.8% (22/2603) of non-capsulated and none of the 402 other capsulated strains. Overall, 78.8% of the 6805 isolates were susceptible to all five antibiotics, 19.0% were resistant to one, 1.8% to two, 0.4% to three and none to four antibiotics (tetracycline was not included because of co-resistance with chloramphenicol). Isolates resistant to three antibiotics were evenly spread throughout the study period, with a maximum of three multiresistant isolates identified in any one year. In the most recent year of analysis, 2004, antibiotic resistance for 
500 H. influenzae isolates was: trimethoprim, 11.9%; ampicillin, 11.6%; tetracycline, 1.7%; chloramphenicol, 0.6%; cefotaxime, 0%; and rifampicin, 0%.
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Discussion |
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We have described the largest series of invasive clinical H. influenzae isolates by serotype from adults and children in England and Wales over 20 years. Only isolates submitted to the Haemophilus Reference Unit were included to ensure standardized methodology. It is reassuring to note that resistance to cefotaxime and rifampicin is extremely low (<0.1%). Third-generation cephalosporins are currently the empirical treatment of choice for serious infections because they provide broad-spectrum antimicrobial cover with few serious side effects, while rifampicin is highly effective in eliminating H. influenzae carriage (92% to 97%) and remains the recommended prophylactic agent for preventing secondary H. influenzae disease among contacts.8
Antibiotic resistance rates for clinical H. influenzae isolates in England and Wales are substantially lower than those reported by other European and North American countries, although different methods of antibiotic susceptibility testing have been used in these studies.2,3 BLNAR rates are also much lower than those reported elsewhere—one European study of clinical H. influenzae isolates from 11 countries reported BLNAR rates of 8.8% in 1997/98, 9.6% in 2002/03 and 8.8% in 2004/05, compared with 8.7%, 4.7% and 0% for the same time periods in our study.2 The low resistance rates for cephalosporin, rifampicin and tetracycline along with a downward trend in ampicillin resistance since 1998 is also in contrast to reports from other countries where resistance to commonly prescribed antibiotics is increasing rapidly.2,4 One reason for this decline may be the recent drive in the UK to reduce antibiotic prescription in the community (up to 50% reduction between 1993 and 1999).9
In contrast, trimethoprim resistance has increased significantly since the early 1990s, although rates in our study are still significantly lower than reported in other countries.10 A recent study involving 2712 H. influenzae isolates from 13 countries, for example, reported that 34.5% of the isolates were resistant to trimethoprim/sulfamethoxazole.3 The increase in trimethoprim resistance in our study was associated with younger age, and the timing of this increase coincides with guidance published by the Royal College of Physicians in the early 1990s on the management of urinary tract infections in children. These guidelines recommend prolonged courses of low-dose trimethoprim until radiological investigations are complete.10 Children with renal tract anomalies (e.g. vesico-ureteric reflux) were then advised to continue trimethoprim prophylaxis for several years. These guidelines have therefore resulted in a significant proportion of the childhood population becoming exposed to trimethoprim. The findings in this study raise the possibility that this exposure has resulted in increased trimethoprim resistance among frequently carried bacteria, such as H. influenzae.
Our results have important clinical implications. First, they support the use of third-generation cephalosporins for the empirical treatment of serious bacterial infections. Secondly, rifampicin remains the prophylactic agent of choice for the eradication of H. influenzae among carriers and vulnerable contacts. Thirdly, although the ampicillin resistance rate of 11.6% in 2004 would still be considered too high for empirical treatment, this antibiotic provides a safe and effective therapeutic option if the strain is reported to be ampicillin-susceptible. Finally, the dramatic increase in trimethoprim resistance is of concern and is perhaps a timely reminder of the need for the judicious use of antibiotics.
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Funding |
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This study did not receive any funding. S. L. was awarded a competitive 2 year European Society for Paediatric Infectious Diseases (ESPID) Fellowship in 2005 to study invasive Haemophilus influenzae infections in children.
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Transparency declarations |
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S. L. and M. P. E. S. have received funding from vaccine manufacturers to attend scientific meetings. P. T. H. is an investigator for clinical trials conducted on behalf of St George's, University of London, sponsored by vaccine manufacturers, including manufacturers of Hib vaccines. He has also received assistance from vaccine manufacturers to attend scientific meetings. M. E. R.: none to declare.
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References |
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Sharland M, Kendall H, Yeates D, et al. Antibiotic prescribing in general practice and hospital admissions for peritonsillar abscess, mastoiditis, and rheumatic fever in children: time trend analysis. BMJ (2005) 331:328–9.
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