Department of Infection, Guys, Kings and St Thomas School of Medicine, Kings College London, St Thomas Hospital, London SE1 7EH, UK
Received 7 October 2003; returned 5 December 2003; revised 22 December 2003; accepted 8 January 2004
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Abstract |
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Methods: Antimicrobial susceptibilities were analysed for the 6 years 19952000. Gentamicin-resistant isolates from 1995 and 2000 were typed by a repetitive element sequence-based PCR (Rep-PCR) method.
Results: Resistance rates for all agents and all organisms were higher in isolates from inpatients than in those from outpatients or general practice. For most agents and most species there was a trend for a highly significant linear increase in resistance over the study period, and there was significant cross-resistance between different agents. Increases in resistance were especially marked in Klebsiella, Enterobacter and Acinetobacter spp., organisms that tend to cause outbreaks of hospital cross-infection. For example, the increases in gentamicin resistance in isolates from inpatients was from 2.9% to 23.5% for Klebsiella spp., from 0.3% to 20.8% for Enterobacter spp. and from 10.1% to 42.2% for Acinetobacter spp. There was much less increase in acquired resistance in Escherichia coli and Pseudomonas aeruginosa, organisms that tend to cause endogenous infections, with gentamicin resistance in isolates from inpatients increasing from 0.4% to 3.2% for E. coli and decreasing from 4.6% to 3.6% for P. aeruginosa. Rep-PCR typing showed considerable diversity amongst gentamicin-resistant isolates of E. coli and P. aeruginosa, but dominance by a limited number of presumably epidemic types of gentamicin-resistant isolates of the other species.
Conclusions: Multiple antibiotic resistance has increased dramatically in some hospital isolates, and appears to be associated with hospital cross-infection.
Keywords: Enterobacteriaceae, Pseudomonas, Acinetobacter, gentamicin, ciprofloxacin
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Introduction |
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Repetitive element sequence-based PCR (Rep-PCR) is a method for fingerprinting bacterial genomes by examining patterns obtained from PCR amplification of repetitive DNA elements in bacterial genomes.4 Two main sets of repetitive elements are used for typing purposes: repetitive extragenic palindromic (REP) elements and enterobacterial repetitive intergenic consensus (ERIC) sequences, which, despite their name, can be used for a wider range of bacteria than just the Enterobacteriaceae.4
In this paper we report the frequency of resistance in opportunistic Gram-negative bacteria from Guys and St Thomas Hospitals in the years 19952000, following the reorganization of hospital provision in London in the mid-1990s, and results of molecular typing by Rep-PCR to determine the extent to which resistance can be attributed to cross-infection.
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Methods |
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Antimicrobial susceptibility results for Escherichia coli, Pseudomonas aeruginosa and Klebsiella, Enterobacter and Acinetobacter spp. isolates from the microbiology laboratory computer system of the Guys and St Thomas Hospitals NHS Trust were analysed for the 6 years 19952000. Duplicate isolates of the same organism from the same patient within a calendar year5 were eliminated by a computerized system on the basis of patients names, identification numbers and organism identification. Surveillance specimens (e.g. those in which gentamicin-resistant stool isolates were sought, but gentamicin-susceptible isolates were ignored) were excluded from the calculations. Isolates were divided into three groups: those from inpatients, those from outpatients and those from general practice (GP) patients in the community. Results were also calculated for all (total) isolates.
Exclusion of duplicates and calculation of resistance rates were performed on the four groups separately. Consequently, results for the same organism from the same patient may appear in each of the inpatient, outpatient and GP groups. However, calculations for all isolates and for cross-resistance were performed on the whole organism database with all duplicates excluded.
Susceptibility testing methods
Antimicrobial susceptibility was determined by disc diffusion methods. The comparative method6 was used until the autumn of 2000, after which the BSAC method7 was introduced. Intermediate categories of susceptibility or resistance were not used in either method. Although the BSAC method allows an intermediate category for gentamicin, amikacin and ciprofloxacin against P. aeruginosa, any such isolates were recorded as resistant. Gentamicin was not tested against isolates from GP patients after 1998. Meropenem was tested against P. aeruginosa from August 1997 to November 1999; imipenem was tested at other times. For isolates of E. coli and Klebsiella spp. from GP patients, cefuroxime was only tested if the isolate was resistant to cefadroxil; for the purposes of this paper, we have taken susceptibility to cefadroxil also to indicate susceptibility to cefuroxime. Because isolates of Enterobacter spp. and Acinetobacter spp. from GP patients were often reported as cefuroxime resistant on the basis of their identity, we have omitted results for cefuroxime for this group of organisms.
Rep-PCR typing
Rep-PCR typing was performed on all the gentamicin-resistant inpatient isolates that were available from 1995 and 2000. DNA was extracted from organisms grown in brainheart infusion by heating at 95°C for 30 min in the presence of 0.05 M NaOH and 1% Triton X-100, followed by neutralization with 0.2 M TrisHCl (pH 8.0). The PCR mixture consisted of 10 mM TrisHCl (pH 8.8), 1.5 mM MgCl2, 50 mM KCl, 0.1% Triton X-100, 0.2 mM of each of the four dNTPs, 2 µM of each of the two primers (ERIC2: 5'-AAGTAAGTGACTGGGGTGAGCG-3'; REP2-Dt: 5'-NCGNCTTATCNGGCCTAC-3'), 0.4 U of DyNAzyme II thermostable DNA polymerase (GRI, Braintree, UK) and 2 µL of DNA extract in a total volume of 20 µL. After initial heating to 94°C for 4 min, the mixture was subjected to 45 cycles of amplification (94°C for 1 min, 42°C for 1 min, 68°C for 8 min), followed by 15 min at 68°C. The products were mixed with a loading buffer and subjected to electrophoresis in 1.5% agarose containing 0.5 mg/L ethidium bromide in 44.5 mM Trisborate buffer (pH 8.1) containing EDTA (1 mM) for 4 h at 3.3 V/cm.
Statistical methods
Results for each organism and antibiotic were analysed by patient group for each year from 1995 to 2000. The gentamicin susceptibility of GP patient isolates (and consequently of total isolates) was analysed only for 19951998. Changes in resistance rates over the study period were analysed by the 2 test for trend.8 We took a P value of
0.01 to indicate statistical significance for this test.
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Results |
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Most isolates of E. coli were from GP patients, with the rest equally divided between inpatients and outpatients. Amoxicillin resistance was in the range 4353%, and was slightly more frequent in isolates from inpatients than in others. There was a slight increase in amoxicillin resistance over the 6 year period for all groups, but none of these differences was significant. Resistance rates in E. coli to cefuroxime, ciprofloxacin and gentamicin were low, but mostly increased significantly over the study period. Cefuroxime resistance increased more than three-fold in inpatient isolates, reaching 6.3% in 2000, and rose at least two-fold in the other two groups. There were similar changes in ciprofloxacin resistance. Gentamicin resistance rose eight-fold in inpatient isolates, from 0.4% in 1995 to 3.2% in 2000, and nearly five-fold in outpatients; it remained at 0.5% from 1995 to 1998 for GP isolates.
Klebsiella spp.
Most isolates were Klebsiella pneumoniae, and approximately half were from inpatients. Almost all isolates were resistant to amoxicillin (results not shown). Resistance to cefuroxime was infrequent in klebsiellas from all patient groups in 1995. Resistance increased significantly by 2000, reaching 33% of inpatient isolates (an eight-fold increase) and 12% and 4% of outpatient and GP isolates, respectively. There was a similar rise in gentamicin resistance in both inpatients and outpatients, but the small rise in resistance in GP isolates between 1995 and 1998 (from 0% to 1.2%) was not statistically significant. A similar pattern was seen for ciprofloxacin resistance, which rose significantly in inpatients and outpatients, but there was only a small and statistically insignificant rise in quinolone resistance in GP patient isolates.
Enterobacter spp.
Approximately 70% of the isolates of Enterobacter spp. were from inpatients. Most isolates (>96%) were resistant to amoxicillin (results not shown). Resistance to cefuroxime was much more frequent than in klebsiellas, averaging 30% for inpatient and outpatient isolates considered together in 1995, and rising significantly to
70% in 2000, with the highest rate in inpatient isolates. Gentamicin resistance was rare in 1995, but rose over the study period, dramatically so in inpatient isolates, which showed 21% resistance in 2000. However, gentamicin resistance reached only 46% in 1999 and 2000 in outpatient isolates.
Acinetobacter spp.
Acinetobacters were isolated relatively infrequently, and about two-thirds were from inpatients. There were significant trends of increasing resistance to all four antimicrobials between 1995 and 2000 amongst inpatient isolates: amoxicillin resistance rates increased by one and a half times to reach 83% in 2000; cefuroxime resistance rates nearly doubled to 86%; ciprofloxacin resistance increased two and a half times to 48%; and gentamicin resistance quadrupled to 42%. Resistance rates in isolates from outpatients and GPs were lower and the increases over the 6 years less marked, but the numbers of isolates were small.
P. aeruginosa
Approximately half of the P. aeruginosa isolates were from inpatients. Resistance rates to gentamicin, amikacin, ciprofloxacin, ceftazidime and imipenem/meropenem were relatively low; in inpatient isolates in 2000, being about 4%, 0.3%, 9%, 0.6% and 5%, respectively. Furthermore, there was no significant trend for a linear increase in resistance to any of these agents over the 6 year study period. Indeed, mathematically the most significant change in trend was for a slight fall in ceftazidime resistance in GP isolates from 0.4% resistance in 1995 to 0.3% in 2000. However, there was an unexplained jump in ceftazidime resistance to 67% in isolates from all patient groups in 1999, which skewed the results; the trend was not significant if results from this year were omitted. The closest to a significant upward trend was an increase in the imipenem/meropenem resistance rate in all patient isolates from 2.5% in 1995 to 3.8% in 2000.
Cross-resistance
There was considerable cross-resistance between gentamicin and other compounds for Enterobacteriaceae and Acinetobacter spp. (Table 2). Except when the organism was almost universally resistant to a compound (e.g. amoxicillin resistance in Klebsiella spp.), gentamicin-resistant isolates were very much more likely to be resistant to co-amoxiclav, cefuroxime and ciprofloxacin than gentamicin-susceptible ones.
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Table 3 summarizes the increases in multiply resistant isolates. As when results for individual compounds were examined, the increases were most marked for Klebsiella spp., Enterobacter spp. and Acinetobacter spp.
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Table 4 shows the results of molecular typing by Rep-PCR on the gentamicin-resistant isolates from inpatients available from the years 1995 and 2000. There were predominant types of Klebsiella spp., Enterobacter spp. and Acinetobacter spp. in 2000, each accounting for 5670% of the isolates. In addition, there was a second fairly common type in klebsiellas (13% of isolates), which, together with type 1, accounted for 70% of the isolates. In contrast, no single type predominated in E. coli or P. aeruginosa. In 1995, when there were fewer resistant isolates, there were no predominating types of Klebsiella spp. or Acinetobacter spp. either.
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Discussion |
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E. coli may cause outbreaks of hospital infection, recognized by clusters of resistant isolates;1214 however, when multiply antibiotic-resistant strains of E. coli isolated from hospital infections are analysed, they are usually found to be genetically diverse.1518 The molecular typing results (Table 4) confirm this for our resistant isolates in 1995 and 2000. Hospital isolates are thus effectively community ones. E. coli can acquire resistance to the cephalosporins by acquisition of genes for the production of extended-spectrum ß-lactamases,1923 and to quinolones by mutation,24 but such resistance has remained uncommon in our isolates.
Resistance rates in P. aeruginosa were low and generally showed no significant increase over the 6 year period. Resistance to gentamicin in inpatient isolates was 4% and to amikacin, 0.3%. Aminoglycoside resistance rates in this organism have always been low in our hospital, despite widespread use of gentamicin: in hospital-acquired strains of P. aeruginosa isolated from blood,11 there was almost no aminoglycoside resistance in the 1970s, and very little in the 1980s.
Although P. aeruginosa is a common cause of hospital-acquired infection, the low rate of antimicrobial resistance in our isolates may be because, like E. coli, it tends to cause endogenous infections rather than cross-infection.25,26 The molecular typing results suggest that this was the case with our isolates, at least in 1995 and 2000 (Table 4). Furthermore, although P. aeruginosa may sometimes receive antimicrobial resistance genes by plasmid transfer, most acquired resistance to aminoglycosides, carbapenems, fluoroquinolones and newer cephalosporins is the result of genetic mutation.2733 Carriage of clinically undetectable resistant mutants of P. aeruginosa may be common in normal people, and this resistant population may emerge under antibiotic pressure during hospitalization.25,26
In contrast, Klebsiella and Enterobacter spp. showed significant and sometimes dramatic increases in antimicrobial resistance and multiple resistance between 1995 and 2000. In inpatient isolates, cefuroxime resistance in klebsiellas rose from 4% to 33%, gentamicin resistance from 3% to 23% and ciprofloxacin resistance from 2% to 17%. There were similar changes in Enterobacter spp., except that cefuroxime resistance started at a higher rate (32% in 1995) and rose to 75% in 2000.
These two species tend to survive in the environment, colonize mucous membranes, and to be transferred from patient to patient on staff hands. They are all inherently resistant to ampicillin/amoxicillin; Enterobacter also tends to be inherently resistant to earlier cephalosporins, and may develop chromosomal resistance to newer ones.34,35 These species also have a great facility for acquiring and disseminating resistance plasmids,36,37 which in recent years often encode resistance to aminoglycosides and newer cephalosporins,20,38 and for causing outbreaks of multiply resistant nosocomial infection. We have seen several such outbreaks involving klebsiellas and enterobacters in our hospital over the last few years,3942 following the introduction of resistant strains by transfer of patients from other hospitals. These factors have presumably contributed to the increasing rates of resistance seen in our isolates of Klebsiella spp. and Enterobacter spp. between 1995 and 2000. The molecular typing results for Klebsiella spp. and Enterobacter spp. indicate that the high frequencies of gentamicin resistance in 2000 were associated with the dissemination of relatively few resistant strains (Table 4).
Acinetobacter spp. are increasingly common hospital pathogens and are becoming increasingly multiply resistant.4345 Although we did not isolate large numbers of these organisms, they showed significant increases in resistance to amoxicillin, cefuroxime, gentamicin and ciprofloxacin during the 6 year study period. Amongst inpatient isolates, resistance rates to these agents increased between one and a half times and four times, all starting from relatively high rates of resistance in 1995, and reaching >80% for amoxicillin and cefuroxime and >40% for gentamicin and ciprofloxacin by 2000.
Acinetobacters have a similar epidemiology to the Klebsiella/Enterobacter group, but, in addition, survive well in dust and can be transmitted in air. We have experienced outbreaks of infection with these organisms at our hospital, although less frequently than with klebsiellas. As for Klebsiella spp. and Enterobacter spp., the molecular typing results indicate that the high frequencies of gentamicin resistance in 2000 were associated with a limited number of epidemic strains (Table 4).
In conclusion, both E. coli and P. aeruginosa exhibited relatively low rates of acquired antimicrobial resistance, which increased only slightly or not at all between 1995 and 2000, and the resistant strains were heterogenous. In contrast, Klebsiella, Enterobacter and Acinetobacter spp. showed dramatic increases in acquired resistance rates to multiple agents over the 6 year study period, and during 2000 there were relatively few types amongst the resistant strains. It can be argued that E. coli and P. aeruginosa are relatively infrequent recipients of resistance plasmids and do not commonly cause hospital cross-infection. In contrast, Klebsiella, Enterobacter and Acinetobacter spp. often acquire plasmid-borne resistance genes to aminoglycosides and ß-lactams, and in our hospital were commonly involved in hospital outbreaks. Thus, the alarming increase in multiple antimicrobial resistance in this group can be explained partly by hospital cross-infection. Unless effective control strategies are implemented to reduce hospital cross-infection and control the use of antibiotics, this trend towards multiple antibiotic resistance in Gram-negative bacteria will continue, and may increasingly involve non-hospital patients.
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Footnotes |
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