Spencer, R. C., Wheat, P. F., Magee, J. T. & Brown, E. H. ... Allen, K. D. & Anson, J. J. (1996). ... Millar, M. R., Brown, N. M., Tobin, G. W., Murphy, P. J., Wind-.
Journal of Antimicrobial Chemotherapy (1997) 40, Suppl. A, 11–18
JAC
Pneumococcal resistance in the UK Colin E. Goldsmith, John E. Moore and Philip G. Murphy Bacteriology Department and Northern Ireland Public Health Laboratory, Belfast City Hospital, Lisburn Road, Belfast BT9 7AD, UK The first case reports of infection with penicillin-resistant pneumococci (PRP, MIC 0.1 mg/L) and multidrug-resistant pneumococci were made in Australia in 1967 and South Africa in 1977, respectively. Since this time these organisms have spread to become a worldwide problem. In Europe PRP prevalence rates of up to 40% have been reported from Spain and 58% from Hungary, although there has been considerable national, regional and local variation in these figures. Until recently the UK was considered to have low prevalence of PRP. As recently as 1990, 100% of 7255 strains of pneumococci from 61 centres across the UK were found to be penicillin sensitive. However, there have now been several reports of significant and rising levels of resistance nationwide. Erythromycin resistance has also risen from 2.8% to 8.6% between 1990 and 1995 in England and Wales. At the Northern Ireland Public Health Laboratory (NIPHL) 3171 strains of pneumococci were examined using the oxacillin screening test between 1988 and 1995, during which time the annual rate of penicillin resistance was found to increase from 1% to 10.6%. The proportion of PRP with high-level resistance (MIC 1 mg/L) increased from 0% to 36% and levels of PRP cross-resistance to cephalosporins and ciprofloxacin were 89% and 78%, respectively, which are amongst the highest in the UK. Similar rates of penicillin resistance have now been reported from several geographically disparate regions in the UK including Liverpool, Manchester and London. The number of laboratories in England and Wales reporting the isolation of PRPs to the Central Public Health Laboratory increased from 23 (3%) in 1987 to 72 (21%) in 1991 and a recent study from this reference laboratory showed that the prevalence of pneumococcal resistance to penicillin had increased 2.5-fold between 1990 and 1995. Clearly both PRP and multidrug-resistant pneumococci are increasing in prevalence in the UK, and this increase is likely to continue. A recent model of the evolution of national PRP prevalence rates describes a slow emergence phase, followed by an exponential growth phase of around 10 years reaching a stationary phase when the proportion of PRP reaches 50%. It is possible that the UK is currently at the beginning of the exponential growth phase of PRP. This has implications for the future treatment of pneumococcal infections in this country and emphasizes the need for new anti-pneumococcal agents. The new quinolone grepafloxacin, which has an MIC90 of 0.25 mg/L for pneumococci, may represent a future alternative oral treatment for multidrug-resistant strains. The activity of this antibiotic against 70 PRPs is compared with that of two other quinolones and macrolides.
Introduction
New Guinea soon after.4 By 1977 the first clinical cases of infection with multiply antibiotic resistant pneumococci were reported from South Africa.5 These organisms were resistant to penicillin, erythromycin and chloramphenicol and multidrug resistance in pneumococci has since been defined as resistance to three or more different classes of antibiotics. In the UK the first report of PRP was in 1976 from a patient with meningitis;6 imported multi-resistant strains followed in 19787 and in 1980 a PRP strain was isolated from a child who had never travelled abroad.8
Streptococcus pneumoniae, with diminished susceptibility to penicillin (or penicillin resistant pneumococci (PRP)) were first isolated in vitro by serial subculture of the organism on to media containing increasing concentrations of penicillin in 1945, just after this antibiotic was first used.1 PRP were not recovered from clinical specimens until 20 years later in 1965 in Boston, when their clinical significance was not realized.2 The first clinical case reports of infection with PRP came from Australia in 19673 and Papua 11 © 1997 The British Society for Antimicrobial Chemotherapy
C. E. Goldsmith et al. Over the years penicillin and multi-drug resistant pneumococci have become a worldwide problem. In Europe penicillin resistance rates of up to 50% and 58% have been documented amongst pneumococci from Spain 9 and Hungary,10 respectively. There has been considerable national, regional and local variation in these figures. Until recently the UK, like the rest of Northern Europe, was considered to have a low prevalence of PRP. As recently as 1990, no PRP were detected in a survey of 7255 pneumococcal strains from 61 centres across the UK.11 Since then, there have been numerous reports of significant and rising levels of antibiotic resistance in pneumococci nationwide, as well as several hospital outbreaks.12–21 Recent trends in the isolation of PRP in the Northern Ireland region of the UK are reported and compared with reports from the rest of Britain. These trends indicate that problems may arise with antibiotic treatment of PRP infections in the community using oral agents. The in-vitro anti-pneumococcal activity of the quinolone grepafloxacin is compared with that of other quinolones and macrolides.
In the second recent study the susceptibilities of 136 penicillin-sensitive pneumococci (PSP) isolated at the NIPHL were investigated. The MICs of the following antibiotics were determined using the Sensititre Microbroth System (Accumed International East Grinstead, UK): penicillin, amoxycillin, erythromycin, doxycycline, chloramphenicol, ceftriaxone and ciprofloxacin. Microtitre trays containing Mueller–Hinton Broth supplemented with cations and 2.5% lysed horse blood were inoculated with a final concentration of 10 5 cfu/mL and incubated overnight at 37°C in air.23 Finally, the activity of grepafloxacin was compared with that of two other quinolones and three macrolides against 60 local PRP and 10 PRP from London (obtained from the North Middlesex Hospital, London, courtesy of Dr J. Ambler). The MICs of grepafloxacin, ciprofloxacin, ofloxacin, erythromycin, azithromycin and clarithromycin were determined by Etest methodology (A.B. Biodisk, Solna, Sweden) utilizing Mueller–Hinton agar supplemented with 5% blood and overnight incubation at 37°C in 5% CO2. Interpretation of antibiotic susceptibilities was according to British Society for Antimicrobial Chemotherapyspecified breakpoints.24
Methods -Haemolytic streptococci exhibiting characteristic colonial morphology and susceptibility to optochin (ethylhydrocuprein) were identified as S. pneumoniae. All pneumococci isolated from clinical specimens at the Northern Ireland Public Health Laboratory (NIPHL) between 1988 and 1995 were tested for penicillin resistance using the oxacillin screening test. The zones of inhibition around 1 g oxacillin discs on Diagnostic Sensitivity Test Agar (DST Agar, Oxoid, Basingstoke, UK) were measured after overnight incubation at 37°C in atmosphere of 95% air and 5% CO 2. Those isolates exhibiting zone diameters of 19 mm were defined as penicillin resistant. In 1988 Lafong et al.22 serogrouped or serotyped isolates of pneumococci from Northern Ireland and determined MICs of penicillin, ampicillin, erythromycin, tetracycline, chloramphenicol and cephradine against them. Results from this study were compared with two more recent studies performed on strains isolated in this laboratory. In the first study 42 strains isolated between 1994 and 1995 and screened as penicillin resistant by the disc diffusion method were investigated (by the Streptococcus, Diphtheria and Antibiotic Reference Units of the Central Public Health Laboratory, Colindale, UK). Serogrouping and serotyping were performed using slide agglutination with capsular typing sera (Statens Serum Institute, Copenhagen, Denmark). MICs were determined by means of an agar incorporation method utilizing doubling dilutions of antibiotic in DST agar supplemented with 5% horse blood and an inoculum of 104 cfu per spot. Plates were incubated for 20 h at 37°C in air. The activities of penicillin, ampicillin, erythromycin, tetracycline, chloramphenicol, cefotaxime and ciprofloxacin were determined against the 42 PRP.
Results In total 3171 isolates of S. pneumoniae were identified and screened for penicillin resistance between 1989 and 1995. Although only a small proportion of the total (69/3171 (2%)) were found to be oxacillin resistant, the annual percentage has risen dramatically from 0.8% in 1988 to 10.6% in 1995 (Table I). The MICs of the 488 pneumococci tested by Lafong et al.22 in 1988 are shown in Table II. Only 4/488 isolates (0.8%) demonstrated diminished susceptibility to penicillin at this time. No high-level penicillin resistance was detected (MIC 2 mg/L), as all four PRP demonstrated
Table I. Number (percentage) of isolates of pneumococci that were resistant or sensitive to penicillin, NIPHL 1988–95 (cf. reference 12)
12
Year
Number (%) resistant
Number sensitive
1988 1989 1990 1991 1992 1993 1994 1995
4 (0.8) 0 4 (1.0) 0 0 3 (0.9) 12 (3.1) 46 (10.6)
484 410 400 395 377 345 372 388
Pneumococcal resistance in the UK intermediate penicillin resistance (0.1 MIC 1 mg/L). Cross-resistance to cephalosporins at this stage was difficult to assess, as the cephalosporin investigated in this study was cephradine, which has poor activity against PRP. No erythromycin resistance was demonstrated at this time. Chloramphenicol resistance was low at 5.4% and
resistance to tetracycline was the highest of those antibiotics tested at 12.1%. The results of the antibiotic susceptibility tests performed against the 42 PRP and 136 PSP isolated between 1992 and 1995 are shown in Tables III and IV, respectively. A significant proportion (36%) of the PRPs demonstrated
Table II. In-vitro activity (mg/L) of six antibiotics against 488 strains of pneumococci isolated at the NIPHL in 1988 (cf. reference 22) Antibiotic Penicillin Ampicillin Erythromycin Tetracycline Chloramphenicol Cephradine
MIC50
MIC90
0.06 0.12 0.12 1 4 4
0.06 0.12 0.12 2 4 4
MIC range 0.06–1 0.12–4 0.12 1– 8 4–32 4–32
Table III. In-vitro activity (mg/L) of 10 antibiotics against 42 penicillin-resistant pneumococci isolated at the NIPHL (1994–5)
Antibiotic
MIC range
Penicillin Ampicillin Erythromycin Tetracycline Chloramphenicol Cefotaxime Ciprofloxacin Rifampicin Vancomycin Teicoplanin
0.25–2 0.5–4 16 8 8 0.125–2 2–>8
