A comparison of antimicrobial resistance rates in Gram-positive pathogens isolated in the UK from October 1996 to January 1997 and October 1997 to January 1998

J. Andrewsa,*, J. Ashbya, G. Jevonsa, T. Marshallb, N. Linesc and R. Wisea

a Department of Medical Microbiology, City Hospital NHS Trust, Birmingham B18 7QH; b Department of Public Health and Epidemiology, University of Birmingham B15 1BR; c Pathology Computing Department, City Hospital NHS Trust, Birmingham B18 7QH, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Rates of resistance for two consecutive years for 28 centres (10 Teaching, nine Associate Teaching and nine District General hospitals) in the UK were compared. Combined rates of resistance for each of the hospital types of Staphylococcus aureus to methicillin revealed an increase in the rate of resistance in Teaching hospitals (12.5% year 1, 23.5% year 2), but, for Associate Teaching and District General hospitals rates fell (Associate Teaching 19.1% year 1, 11.9% year 2; District General 16.5% year 1 and 11.3% year 2). Using conventional methodology to determine MICs, no strain was considered to have reduced susceptibility to vancomycin. Among coagulase-negative staphylococci, increased resistance was observed for Staphylococcus epidermidis to rifampicin, for Staphylococcus haemolyticus to clindamycin, for Staphylococcus saprophyticus to penicillin and for Staphylococcus spp. to clindamycin, methicillin and rifampicin. For Streptococcus pneumoniae an upward trend in low-level resistance to penicillin was observed (18 of the 28 centres), however, for high-level resistance the trend was in the opposite direction (only four centres showed an increase). For Enterococcus faecalis there was a trend to a fall in levels of resistance, the only exception being an increase in high-level gentamicin resistance (10.5% year 1, 15.1% year 2, P = 0.0388). For Enterococcus faecium rates of resistance were not significantly different except for increases in resistance to nitrofurantoin and rifampicin.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Resistance amongst bacterial pathogens is perceived to be an ever increasing issue. However, it is difficult to assess the magnitude of the problem because studies are rarely designed to survey the same centres at repeated pre-determined time intervals and therefore it is hard to differentiate between sporadic fluctuations and sustained increases in patterns of resistance.

Antimicrobial resistance in Gram-positive pathogens isolated between October 1996 and January 1997 in 10 Teaching, 10 Associate Teaching and 10 District General hospitals in the UK has been reported previously.1 This study was the first of three surveys monitoring resistance rates over a 4 month period in three consecutive years and the results from this survey have provided a baseline level of resistance to which subsequent rates can be compared. In this, the second study, rates of resistance for Grampositive pathogens isolated between October 1997 and January 1998 were determined and then compared with the first survey. However, for unforeseen reasons, one of the Associate Teaching and one of the District General hospitals were unable to take part in the second study. For this reason the comparisons shown are for the 28 hospitals that completed both surveys.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Sample collection and organism identification

As in the previous study, laboratories collected consecutive clinically significant isolates comprising 60 Staphylococcus aureus, 60 coagulase-negative staphylococci, 40 Streptococcus pneumoniae and 20 enterococci. Laboratories were asked to exclude duplicate isolates from the same patient and multiple isolates from a cross-infection source. Identification of the isolates was confirmed using the same procedures as those used in year 1.

MICs

MICs were determined as described previously:1 briefly, Iso-Sensitest agar (Oxoid, Basingstoke, UK) was used as basal medium (supplemented with 5% defibrinated horse blood for testing pneumococci), an inoculum of 104 cfu/ spot and incubation at 35–37°C in air, except for pneumococci where the atmosphere was enriched with 4–6% CO2. Methodology was somewhat different when determining sensitivity of staphylococci to methicillin/oxacillin: in this instance, Mueller–Hinton agar (Difco Laboratories, West Molesey, UK), an inoculum of 106 cfu/spot and incubation at 30°C were employed.

Interpretation of resistance

The same criteria for interpretation of sensitivity were used as those in the previous survey, i.e. using published MIC breakpoints to separate the sensitive and resistant populations.

Statistical analysis

To ascertain whether there was a significant change in the level of resistance during study periods one and two, the data were subjected to statistical analysis ({chi}2 and Fisher's exact test) using EpiInfo, a program available from the Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
S. aureus

The combined rate of resistance to methicillin in the second year for the 10 Teaching hospitals was almost double that seen for the first survey period (12.5% year 1 and 23.5% year 2, P <0.0001) (Table IGo). Four centres in particular had dramatic increases in levels of resistance: Belfast (8.35 year 1, 28.3% year 2, P = 0.009), Cambridge (10.2% year 1 and 25% year 2, P = 0.05), Edinburgh (6.7% year 1, 25% year 2, P = 0.01) and Southampton (1.7% year 1, 56.7%, P <0.0001), which influenced the combined rate of resistance.


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Table I. Rates of resistance to methicillin (MIC breakpoint 4 mg/L) for S. aureus for two consecutive years depending on geographical location and type of hospital
 
For the Associate Teaching hospitals the combined rate of resistance fell from 19.5% in year 1 to 11.9% in year 2 (P = 0.0006) (Table IGo). Data for three centres influenced the reduction in levels of resistance: Cardiff (13.3% year 1, 1.7% year 2, P = 0.03), Birmingham (39% year 1, 20% year 2, P = 0.03) and Londonderry (56.7% year 1, 10% year 2, P <0.0001).

For the District General hospitals there was a fall in the level of resistance for the combined data (16.5% year 1, 11.3% year 2, P = 0.008) (Table IGo). Reductions in resistance rates were seen at two centres: Wolverhampton (56.3% year 1, 23.3% year 2, P = 0.0003) and Alexandria (13.6% year 1, 3.3% year 2, P = 0.05). However, a substantial rise in the level of resistance was seen for Merseyside (1.7% year 1, 16.7% year 2, P = 0.01).

A summary of resistance rates for the combined data for each type of hospital for antimicrobials other than methicillin is shown in Table IIGo. For the Teaching hospitals statistically significant rises in resistance were seen for ciprofloxacin (14.9% year 1, 23.8% year 2, P <0.0001), clindamycin (4.5% year 1, 7.3% year 2, P = 0.04), erythromycin (17.9% year 1, 26.5% year 2, P = 0.0003) and rifampicin (0.5% year 1, 2.3% year 2, P = 0.01). For the Associate Teaching and District General hospitals statistically significant changes in resistance were only observed for fusidic acid (5.2% year 1, 9.4% year 2, P = 0.01) and penicillin (72.2% year 1, 83.7% year 2, P <0.0001), respectively. Although not considered statistically significant, three organisms isolated in year 2 were of interest. Two strains, one from each of the Teaching and District General hospitals, were resistant to quinupristin/dalfopristin (MICs of 4 mg/L) and one strain from an Associate Teaching hospital had an MIC of teicoplanin one dilution above the breakpoint of 4 mg/L (identification confirmed by API ID32—bioMérieux, Basingstoke, UK). Using a conventional MIC determination method no strains were considered resistant to vancomycin.


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Table II. Summary of resistance for S. aureus to a variety of antimicrobials for Teaching, Associate Teaching and District General hospitals in the UK in two consecutive years
 
Coagulase-negative staphylococci

Although disparate staphylococcal species were submitted for investigation, only combined data for the 28 centres for Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus spp. and Staphylococcus saprophyticus were compared, as the data for species other than these were considered insufficient for meaningful statistical analysis. Numbers submitted by the participating laboratories and a summary of rates of resistance are shown in Table IIIGo.


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Table III. Comparison of rates of resistance for staphylococci to a variety of antimicrobials for two consecutive years; data combined for 10 Teaching, nine Associate Teaching and nine District General hospitals in the UK
 
S. epidermidis

Resistance rates were similar between years 1 and 2 except for rifampicin where a statistically significant rise in resistance was observed (8.6% year 1, 17.9% year 2, P = 0.0004). As in year 1, no resistance to quinupristin/dalfopristin or vancomycin was detected.

S. haemolyticus

Resistance rates for year 1 and year 2 were similar with no significant rises seen except for clindamycin where a rise in resistance from 2.7% in year 1 to 4.6% in year 2 was observed (P = 0.05). For the organisms isolated in year 2 no resistance to quinupristin/dalfopristin, rifampicin or vancomycin was detected.

Staphylococcus species

As in year 1, no resistance to quinupristin/dalfopristin or vancomycin was detected. Significant increases in resistance were, however, seen for clindamycin (year 1 6.7%, year 2 16.9%, P = 0.04), methicillin (year 1 26.7%, year 2 42.4%, P = 0.03) and rifampicin (year 1 3.3%, year 2 14.4%, P = 0.01).

S. saprophyticus

The only significant change in level of resistance was observed for penicillin, where the level of resistance rose from 54.3% in year 1 to 63.3% in year 2 (P = 0.004).

S. pneumoniae

A summary of rates of resistance to penicillin, both low-level (MIC range 0.12–1 mg/L) and high-level (MICs >2 mg/L) are shown in Table IVGo. When data were combined for each hospital type, there was a minor increase in low-level resistance from year 1 to year 2 in the Teaching and Associate Teaching hospitals (Teaching hospitals 2.7% year 1, 6.2% year 2, P = 0.04; Associate Teaching hospitals 2.7% year 1, 8.6% year 2, P = 0.05). However, for District General hospitals, although the combined data showed no significant change in the level of low-level resistance, at individual centres significant differences in rates of low-level resistance were observed with an increase for Merseyside (5% year 1, 35% year 2, P = 0.02) and a decrease for Wolverhampton (13.2% year 1, 0% year 2, P = 0.05). With regard to high-level resistance, no significant differences were observed in the Teaching and District General hospitals. However, for the combined data for Associate Teaching hospitals there was a decline in the level of resistance from 6.5% in year 1 to 1.7% in year 2 (P = 0.0007) and for one of the centres, Birmingham, the level of resistance fell from 17.5% in year 1 to 2.5% in year 2 (P = 0.05).


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Table IV. Rates of penicillin resistance in S. pneumoniae (low-level resistancea and high-level resistanceb) related to geographical location and type of hospital, in two consecutive years
 
Resistance rates for antimicrobials other than penicillin are shown in Table VGo. For the Teaching hospitals a significant increase in resistance between year 1 and year 2 was seen for low-level resistance to ciprofloxacin (1.2% year 1, 4.4% for year 2, P = 0.01) and for erythromycin (4.3% year 1, 8% year 2, P = 0.004). No significant change in rates of resistance was observed for Associate Teaching hospitals. However, for District General hospitals a rise in ciprofloxacin low-level resistance was seen (0% year 1, 5.8% year 2, P = 0.0001).


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Table V. Summary of resistance to a variety of antimicrobials for S. pneumoniae for Teaching, Associate Teaching and District General hospitals surveyed on two consecutive years
 
Enterococci

For Enterococcus faecalis significant decreases in resistance from year 1 to year 2 were seen for dalfopristin/ quinupristin (35.2% year 1, 26.8% year 2, P = 0.005), ampicillin (1.4% year 1, 0% year 2, P = 0.02), chloramphenicol (21.6% year 1, 16.5% year 2, P = 0.04), erythromycin (67.9% year 1, 50.5% year 2, P <0.0001) and rifampicin (37.2% year 1, 30.2% year 2, P = 0.02) (Table VGo). However, a rise in high-level gentamicin resistance from 10.5% in year 1 to 15.1% in year 2 was observed.

No significant changes in rates of resistance were seen for Enterococcus faecium except for nitrofurantoin and rifampicin where rates increased from 29 to 90% (P <0.0001) and 64.5 to 95% (P = 0.008), respectively.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A major advantage of this study was that the same centres were surveyed and that organism identification and MIC determinations were undertaken by a central laboratory, thus removing the doubt that differences might be attributed to methodological variation. However, a criticism which can be levelled at most surveillance studies is the nature of the denominator data, which can introduce a bias, because it is not known why the sample was sent to the laboratory.

With regard to S. aureus, these data have shown that levels of resistance to methicillin were not significantly different between years 1 and 2 for 18 of the 28 centres studied, but in five centres rates of resistance increased and in five rates decreased. For the combined data for each of the hospital types, rates of resistance to methicillin increased in year 2 for the Teaching hospitals and decreased for the Associate Teaching and District General hospitals. For the antimicrobials other than methicillin, generally, the greatest change in rates of resistance between the two years was seen for the isolates from the Teaching hospitals (ciprofloxacin, clindamycin, erythromycin and rifampicin). No S. aureus were resistant to quinupristin/dalfopristin in the first year of survey; however, in year 2 two strains had MICs one dilution above the breakpoint. Of further interest was the multi-resistant strain (resistant to penicillin, ciprofloxacin, clindamycin, erythromycin, gentamicin and rifampicin), which had an MIC of teicoplanin of 8 mg/L, yet was sensitive to vancomycin, quinupristin/dalfopristin and fusidic acid.

For the coagulase-negative staphylococci studied significant changes in resistance rates were not observed except for an increase in resistance of S. epidermidis to rifampicin, of S. haemolyticus to clindamycin, of S. saprophyticus to penicillin and of Staphylococcus sp. to clindamycin, methicillin and rifampicin.

As was seen in year 1, resistance rates for pneumococci to penicillin varied considerably with geographical location. For low-level resistance the trend overall would appear to be upward with 18 of the 28 centres surveyed showing an increase in the rate of resistance between year 1 and year 2. With regard to high-level resistance the trend would appear to be in a downward direction in year 2, with only four centres showing increases in rates of resistance compared with 22 centres with falls in resistance rate. The Alexander Project has surveyed the rates of resistance of S. pneumoniae to penicillin in the London area annually for 5 years2 and in 1996 found an equal rate of low-level and high-level resistance to penicillin. For the three London hospitals in this survey one centre had similar results with equal rates of low-level resistance and high-level resistance (10%). However, results for the other two centres were somewhat different, with no high-level resistance to penicillin being identified (low-level resistance 7.5 and 11.5%). Differences that are encountered within a relatively small geographical area are of clinical significance, particularly when deciding empirical therapy. For the antimicrobials other than penicillin it is notable that there is an increase in resistance rate for low-level resistance to ciprofloxacin in year 2 in the Teaching and District General hospitals (4.4 and 5.8%, respectively) and an increase in resistance to erythromycin in Teaching hospitals. A gradual increase in resistance to erythromycin has been observed globally,2 and in some countries, notably Spain, resistance has been linked to penicillin resistance (3.8, 52 and 32.3% erythromycin resistance for the penicillin-susceptible, -intermediate and -resistant populations, respectively).2 For the combined data for year 2 (1006 strains), levels of erythromycin resistance for the penicillin-susceptible, -intermediate and -resistant populations of 7.5, 45.5 and 35% were observed, which are similar to those seen in Spain. Interestingly, no such link between penicillin and erythromycin resistance was observed in the 88 strains studied from the London area surveyed by the Alexander Project in 1996.2

For E. faecalis the trend for year 2 was for there to be a fall in rates of resistance or a continuation of the level observed in year 1. The only exception to this was high-level resistance to gentamicin where a rise from 10.5 to 15.1% was observed. For E. faecium, rates of resistance were not significantly different except for increases in resistance to nitrofurantoin and rifampicin.

It is a general view that levels of antimicrobial resistance are increasing amongst all of the genera associated with infectious diseases in man. These data have shown that, indeed, trends are not necessarily always in an upward direction; a pattern also observed in a survey of coagulase-negative staphylococci isolated in seven hospitals in The Netherlands between 1989 and 1995.3 Alterations in antibiotic usage have been shown to correlate with changes in resistance rates.4 However, we are unable to identify the factor or factors that have influenced the fall in resistance rates observed in this study. Perhaps this avenue should be explored when data from the third survey are analysed.


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Table VI. Resistance rates to a variety of antimicrobials for enterococci isolated from Teaching, Associate Teaching and District General hospitals in the UK in two consecutive years
 

    Acknowledgments
 
The following laboratories in the UK participated in this study: Southampton General Hospital, Southampton; Belfast City Hospital, Belfast; Addenbrooke's Hospital, Cambridge; GR Micro Ltd, London; The University of Edinburgh, Edinburgh; Leicester Royal Infirmary, Leicester; St Thomas' Hospital, London; Bristol Royal Infirmary, Bristol; Northern General Hospital, Sheffield; University of Leeds, Leeds; North Middlesex Hospital, London; Llandough Hospital, Cardiff; Altnagelvin Area Hospital, Londonderry; Hope Hospital, Salford; Exeter General Hospital, Exeter; Frenchay Hospital, Bristol; Withington Hospital, Manchester; Lewisham Hospital, London; North Devon District Hospital, Barnstaple; Borders General Hospital, Melrose; Whiston Hospital, Prescot; Trafford General Hospital, Manchester; St Mary's Hospital, Newport; Gloucester Royal Infirmary, Gloucester; Russells Hall Hospital, Dudley; New Cross Hospital, Wolverhampton; Vale of Leven Hospital, Alexandria; City Hospital, Birmingham. We would also like to thank Rhone-Poulenc Rorer for financial support and advice.


    Notes
 
* Corresponding author. Tel: +44-121-507-4228; Fax: +44-121-551-7763. Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Andrews, J., Ashby, J., Jevons, G., Lines, N. & Wise, R. (1999). Antimicrobial resistance in Gram-positive pathogens isolated in the UK between October 1996 and January 1997. Journal of Antimicrobial Chemotherapy 43, 689–98.[Abstract/Free Full Text]

2 . Felmingham, D. & Washington, J. (1999). Trends in the antimicrobial susceptibility of bacterial respiratory tract pathogens—findings of the Alexander Project 1992–1996. Journal of Chemo- therapy 11, Suppl. 1.

3 . de Neeling, A. J., van Leeuwen, W. J., Schouls, L. M., Schot, C. S., van Veen-Rutgers, A., Beunders, A. J. et al. (1998). Resistance of staphylococci in The Netherlands: surveillance by an electronic network during 1989–1995.Journal of Antimicrobial Chemotherapy 41, 93–101.[Abstract]

4 . Rosdahl, V. T., Laursen, H., Bentzon, M. W., Kjaeldgaard, P. & Thomsen, M. (1988). Colonization priority among Staphylococcus aureus strains—correlation with phage-type. Journal of Hospital Infection 12, 151–62.[ISI][Medline]

Received 24 June 1999; returned 2 October 1999; revised 4 November 1999; accepted 23 November 1999