lua
luc
c
anayd
ftihar Köksalg
luh
a
Akdeniz University Faculty of Medicine;
b
Ankara Numune Hospital;
c
Dokuz Eylül University Faculty of Medicine;
d
Erciyes University Faculty of Medicine;
e
Hacettepe University Faculty of Medicine;
f
stanbul University Faculty of Medicine;
g
Karadeniz Technical University Faculty of Medicine;
h
Ondokuz Mayis University Faculty of Medicine,Turkey
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Abstract |
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Introduction |
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Limited data are available concerning infection and mortality rates and antibiotic susceptibility of pathogens from ICUs in Turkey, although studies have yielded higher infection and mortality rates with greater antimicrobial resistance in southern Europe than in northern Europe. 1 ,5
This study was undertaken with the participation of eight hospitals in Turkey to determine the frequency of Gram-negative bacteria isolated in the ICUs and to compare their rates of resistance to selected antibiotics.
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Materials and methods |
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For each isolate, MICs were determined for 13 different antibiotics: imipenem, ceftazidime, ceftazidime- clavulanate, ceftriaxone, cefotaxime, cefepime, cefodizime, cefuroxime, piperacillin/tazobactam, amoxycillin- clavulanate, gentamicin, amikacin and ciprofloxacin. Susceptibility testing was performed on MuellerHinton agar by Etest (AB Biodisk, Solna, Sweden) in accordance with the manufacturer's instructions. Testing procedures were validated following the National Committee for Clinical Laboratory Standards (NCCLS) guidelines, 6 by measuring the MICs of reference strains on a regular basis. For each isolate, the date of sampling, the name of the ICU, a patient identifier and the source of material were recorded. For the data analysis, resistance rates were reported using the NCCLS breakpoints for the susceptible category in which moderately susceptible isolates were classified as resistant. 6
Ceftazidime:ceftazidimeclavulanate MIC ratios have been proposed as a simple
screening test
for ESBL production.
7 Ratios 4 are considered to lack ESBLs and
ratios
16 strongly suggest an ESBL-producing strain. Strains with a ratio of 8 were
excluded from the analysis.
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Results |
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A total of 748 isolates were obtained from 547 patients. Of these, 433 (57.9%) were single isolates, whereas 175 (23.4%) were mixed. Fifty-nine (7.9%) isolates were the initial growth of multiple re-isolations and 81 (10.8%) were obtained from repeat cultures.
Composition of isolate pool by body site
The great majority of organisms were isolated from the respiratory (n = 290; 38.8%) and urinary (n = 231; 30.9%) tracts; 80 (10.7%) were cultured from wounds, drainage fluids and abscesses and 81 (10.8%) from blood.
Composition of isolate pool by species
Each institution submitted 70102 Gram-negative isolates (mean 94). The distribution of isolate pools by species is shown in Table I. Pseudomonasspp. were the most frequently isolated Gram-negative species (26.8%), of which the main isolate was Pseudomonas aeruginosa (22.1%). Klebsiella pneumoniae constituted 66% of Klebsiella spp. (26.2%). Escherichia coli, Acinetobacter spp. and Enterobacter spp. were the other commonly encountered pathogens. Gram-negative non-fermenters and some infrequently isolated microorganisms such as Aeromonasspp. and Salmonella spp. are grouped as `others' in Table I.
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Antibiotic susceptibility rates of isolates
High resistance rates were observed for all antibiotics studied (Table I). Imipenem appeared to be the most active agent against the majority of isolates. Although resistance rates exceeded 50%, ciprofloxacin, cefepime and amikacin were found to be relatively effective. Ceftazidimeclavulanate appeared quite effective against the limited number of pathogens studied, which were mainly Klebsiella spp.
The antibiotic susceptibility of the most commonly isolated pathogens, namely P.
aeruginosa, Klebsiella spp. and E. coli, varied considerably among the
institutions. As the most active agent against P. aeruginosa, imipenem had resistance
rates as low as 14.3% and as high as 80.0% in different ICUs.
Piperacillin/tazobactam and
ceftazidime were moderately effective in some of the hospitals, with resistance rates of
35.785.7% and 17.585.7%, respectively. P. aeruginosa
had resistance rates of
40% to the other antibacterials studied.
Imipenem was consistently effective against Klebsiella spp. However, in one of the centres the rate of resistance was 35.0%, in contrast to rates >12% in the other hospitals. Klebsiella spp. was found to be resistant to the other antibiotics studied, excluding ceftazidime- clavulanate.
E. coli was generally susceptible to all the antibiotics studied except for cefuroxime and amoxycillin- clavulanate in all centres. Imipenem was again the most effective agent.
The resistance rates of initial and repeat isolates were comparable, except for two instances: imipenem resistance appeared to be higher in repeat Acinetobacter spp. (23.9% vs 66.7%; P < 0.01) and P. aeruginosa (52.4% vs 83.3%; P < 0.05) isolates.
Cross-susceptibility patterns of isolates
In this study, multiresistant pathogens were commonly encountered. When ceftazidime-resistant strains were considered, about one-third of P. aeruginosa and more than two-thirds of the other commonly encountered Gram-negative isolates were susceptible to imipenem (Table II). Thirty-four to 52% of ceftazidime-resistant Klebsiella spp., Enterobacter spp. and E. coli were sensitive to cefepime, amikacin, or ciprofloxacin. The piperacillin/ tazobactam susceptibility of these strains was <20%. Amikacin, ciprofloxacin and piperacillin/tazobactam were active against 1722% of resistant P. aeruginosastrains, whereas cefepime had little activity. No antibacterial other than imipenem proved effective against Acinetobacter spp. Ceftazidime-resistant Gram-negative bacteria were uniformly resistant to cefodizime and other cephalosporins.
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According to ceftazidime:ceftazidimeclavulanate MIC ratios, 81 strains were found to lack ESBL production and 112 were determined to be ESBL-producing strains. Ten strains with a ratio of 8 were excluded from the analysis. Amikacin, ciprofloxacin and imipenem were effective against, respectively, 41.3, 48.2 and 92.0% of the ESBL producers. However, only 12.5% of these were susceptible to piperacillin/tazobactam. Cefepime was found to be active against 35.5% of these problem pathogens. Amikacin, ciprofloxacin, cefepime and imipenem were effective against, respectively, 65.4, 71.6, 72.8 and 87.6% of the non-ESBL producers.
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Discussion |
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The species profile of isolated Gram-negative bacteria differed in several ways from European surveys. 1 ,5 ,8 Pseudomonasspp. and Klebsiella spp. were the leading pathogens, with somewhat higher frequencies, E. coli are not as predominant, and Acinetobacter spp. were unexpectedly common in four of the centres (1023%).
Our findings demonstrate very high resistance rates to selected antibacterials including cephalosporins, carbapenems, aminoglycosides and ß-lactam/ß-lactamase in- hibitor combinations, all of which are commonly and effectively used to treat nosocomial infections. Although imipenem stands out as the agent with the lowest resistance rates, rates were still higher than ideal. The addition of clavulanate to ceftazidime appeared to reduce resistance rates dramatically in all centres. Ciprofloxacin, cefepime and amikacin resistance rates exceeding 50% (Table I).
In this study, multiresistant pathogens were more prevalent than in European and USA ICU surveys. 1 ,5 ,8 ,9 Approximately 40% of the isolated microorganisms belong to taxa known to produce inducible Class I ß-lactamase, namely Pseudomonas, Enterobacter, Serratia and Citrobacter spp. and Proteus vulgaris. 10 Cefepime has low ß- lactamase affinity and high resistance to hydrolysis, 11 which may explain its relatively favourable susceptibility rates among cephalosporins in this study. These resistant pathogens, particularly Enterobacter spp. and Serratia spp., maintain their susceptibility to imipenem, for which their resistance rates are <20%.
Taking into account the high resistance rates for ceftazidime, which is stable against Class I
ß-lactamase, ESBL production appears to be a major mechanism of
ß-lactam resistance. Klebsiella spp. and less commonly E. coli are
well-known producers.
12 Ceftazidime is known to be the best single test antibiotic
for the detection of this mechanism.
13 Ceftazidime:ceftazidimeclavulanate MIC ratios
16 have been considered significant for ESBL production.
7
Of the ceftazidime-resistant strains, 61.8% of Klebsiella spp. and 12.1%
of E. coli were found to match this criterion. As
expected, 92.0% and 35.5% of these strains maintained susceptibility to imipenem
and cefepime,
respectively. Tazobactam is expected to inhibit ESBL; therefore piperacillin/tazobactam should
be a good choice for ESBL-producing microorganisms. However, only 12.5% of the
putative
producers isolated in this study were susceptible to piperacillin/tazobactam. A recent report on
ESBL production of Klebsiellaspp. from ICUs in Europe, including two centres in
Turkey, stated that the piperacillin/tazobactam combination inhibited 70% of all putative
producers.
7 In this report, 66% of ESBL- producing Klebsiellastrains from Turkey were found to be resistant to piperacillin/tazobactam, which
is
concordant with our findings. This is probably due to the widespread distribution in Turkey of
non-TEM/SHV ESBLs, such as PER-1, which is resistant to tazobactam.
14
,15
Probably because ESBL genes occur predominantly on large plasmids carrying multiple resistances, 16 putative producers had amikacin resistance rates as high as 58.7%, while non-producers had resistance rates of 35.4% (P > 0.05). Surprisingly, quinolone resistance is known to coexist with ESBL production, but the association is poorly understood because quinolone resistance is chromosome mediated. As is the case for amikacin, we detected 51.8% ciprofloxacin resistance in putative ESBL producers, in contrast to 29.3% resistance in non-producers (P > 0.05).
Although the mechanism of resistance is different and generally due to changes in membrane permeability, ceftazidime-resistant Pseudomonas spp. tend to exhibit cross-resistance with imipenem. 17 In our study, only 33% of ceftazidime-resistant P. aeruginosaisolates were sensitive to imipenem.
Of the 426 cefepime-resistant strains, 79 appear to be susceptible to amikacin. Therefore, when these two agents are administered together, the probability that the responsible pathogen will be susceptible to at least one of the antibiotics becomes 53.6%, compared with 43.0% for cefepime alone. Further activity by synergy may be anticipated. 3 These figures become 47.2% and 58.7% for ciprofloxacin alone and ciprofloxacin plus amikacin, respectively. These findings suggest that the addition of an aminoglycoside may not be a solution to high resistance rates, a consequence of the high prevalence of multi-drug-resistant organisms.
In conclusion, this study has yielded high rates of resistance in aerobic Gram-negative isolates from ICUs in Turkey. Overall resistance rates were lowest with imipenem, followed by ciprofloxacin, amikacin and cefepime.
ESBL production appeared to be a major mechanism of resistance. The ESBLs involved may be different from those commonly encountered in Europe and the USA, because piperacillin/tazobactam has only a weak effect against these organisms, indicating the presence of an enzyme resistant to tazobactam action.
These high rates of resistance leave imipenem as the only reliable agent for the empirical treatment of ICU infections in Turkey. However, the current condition is the result of ineffective hospital infection control and antibiotic policies, which will probably result in increasing rates of resistance to all antibiotics, including imipenem.
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Notes |
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References |
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Received 23 February 1998; returned 27 April 1998; revised 6 July 1998; accepted 9 October 1998