1 Department of Microbiology, Hospital de Móstoles, 28935 Móstoles, Madrid; 2 Department of Microbiology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid; 3 Department of Microbiology, Hospital Universitario de Getafe, Getafe, Madrid, Spain
Received 3 December 2003; returned 22 January 2004; revised and accepted 1 March 2004
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Abstract |
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Methods: The purpose of this work was to test the in vitro susceptibility to ertapenem, ampicillin, cefazolin, cefuroxime, cefotaxime, co-amoxiclav, piperacillin/tazobactam, imipenem, gentamicin, amikacin, fosfomycin, ciprofloxacin and co-trimoxazole of 482 strains of urinary pathogens of the family Enterobacteriaceae isolated from patients in the community of Madrid (40% from males). The distribution was as follows: Escherichia coli (n = 315), Proteus mirabilis (n = 42), Klebsiella spp. (n = 14) and AmpC-producing Enterobacteriaceae (n = 111). The strains studied were selected based on their resistance to quinolones and aminoglycosides, and their production of extended-spectrum ß-lactamases (ESBLs) or AmpC-type ß-lactamases.
Results: All the strains were susceptible to ertapenem, imipenem and amikacin. The MIC90 of ertapenem ranged from a minimum of 0.03 mg/L for Proteus vulgaris and a maximum of 1 mg/L for Enterobacter spp. Ertapenem was the most active of all drugs tested in all cases. On comparing antibiotic resistance among ESBL-producing strains of E. coli (n = 35) and E. coli strains not producing ESBLs (n = 280), statistically significant differences were obtained for ciprofloxacin (P = 0.002) and gentamicin (P = 0.011). Regarding ertapenem, only a slight increase in MIC50 was seen, the value being 0.015 mg/L for strains not producing ESBLs versus 0.03 mg/L for ESBL-producing strains.
Conclusions: In view of its significant antibiotic potency against antibiotic-resistant Enterobacteriaceae, ertapenem may constitute a good therapeutic alternative in urinary infections caused by these pathogens.
Keywords: carbapenems, antibiotic susceptibility, urinary tract infections
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Introduction |
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Ertapenem is a broad-spectrum 1ß-methyl carbapenem with a long plasma half-life that allows for administration of a single daily dose,2,3 while meropenem and imipenem must be administered three to four times a day. The 1ß-methyl substituent of the chemical structure of ertapenem and meropenem confers stability against renal dehydropeptidase I; as a result, co-administration with cilastatin is not required, unlike in the case of imipenem.4 Ertapenem has a broad-spectrum activity, and is active against Gram-positive pathogens most commonly involved in community-acquired infections, Enterobacteriaceae and anaerobes, but has a more limited activity against Pseudomonas aeruginosa, Acinetobacter spp., methicillin-resistant staphylococci and enterococci.58 Similar to the other carbapenems, ertapenem is a ß-lactam with an increased stability against the resistance mechanisms of Enterobacteriaceae, such as production of extended-spectrum ß-lactamases (ESBLs) or AmpC-type ß-lactamases.6,7
Ertapenem is excreted mainly in urine. After administration of ertapenem 1 g to healthy adults, 80% is recovered in urine.3
The presence of resistant or multiresistant Enterobacteriaceae is increasingly common in complicated UTIs, and even in uncomplicated infections, thereby making carbapenems a good treatment alternative. In adults with complicated UTIs requiring initial parenteral therapy followed by adequate oral treatment, ertapenem 1 g daily has been well tolerated and has shown good clinical results.9,10
The purpose of this work was to study the in vitro activity of ertapenem and 12 other antibiotics against recent antibiotic-resistant Enterobacteriaceae isolated from urine samples sent to the laboratory for the diagnosis of urinary infection.
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Materials and methods |
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The strains were selected based on the following criteria: Escherichia coli resistant to ciprofloxacin and/or resistant to gentamicin and/or resistant to cefotaxime and/or producing ESBLs; Proteus mirabilis, Klebsiella pneumoniae and Klebsiella oxytoca resistant to nalidixic acid and/or resistant to gentamicin and/or resistant to cefotaxime and/or producing ESBLs; and AmpC-producing Enterobacteriaceae (mainly Enterobacter, Citrobacter, Morganella, Providencia, Serratia and Proteus vulgaris). Each group was assigned a maximum number of bacteria, so that the final distribution of the 482 strains was as follows: E. coli (n = 315), P. mirabilis (n = 42), P. vulgaris (n = 10), Klebsiella spp. (n = 14), Morganella morganii (n = 39), Enterobacter spp. (n = 41), Citrobacter spp. (n = 6), Serratia spp. (n = 7), Providencia stuartii (n = 6) and Hafnia alvei (n = 2). In the case of multiple isolates from the same patient, only one strain was included.
Each bacterium was identified by the standard laboratory methods, and the MIC of each antibiotic was determined using the agar dilution method following the recommendations of the NCCLS.11 The antibiotics studied were: ampicillin, cefazolin, cefuroxime, cefotaxime, co-amoxiclav, piperacillin/tazobactam, imipenem, ertapenem, gentamicin, amikacin, fosfomycin, ciprofloxacin and co-trimoxazole. MuellerHinton agar (MuellerHinton Agar II; Becton Dickinson and Co., Cockeysville, MD, USA) was used as the culture medium, in which a dilution of the bacterial suspension was inoculated at a McFarland turbidity equivalent of 0.5, representing 104 colony forming units (cfu) per drop applied with a Steers replicator (Craft Machine Inc., Chester, PA, USA). For the determination of fosfomycin MICs, glucose-6-phosphate (25 mg/L) was added to MuellerHinton agar. The plates were incubated for 1824 h at 35°C.
The control strains were P. aeruginosa ATCC 27853, E. coli ATCC 25922 and ATCC 35218, Staphylococcus aureus ATCC 29213, and Enterococcus faecalis ATCC 29212.
The detection of ESBL production was based on the agar diffusion technique according to the standardized conditions of the NCCLS,11 using Etest strips (AB Biodisk, Solna, Sweden) of cefotaxime/cefotaxime clavulanate and ceftazidime/ceftazidime clavulanate, and cefoxitin discs.
Statistical analysis
The 2-test and Fishers exact test were used. A two-tailed P value of
0.05 was considered significant.
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Results |
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The MIC90 of ertapenem ranged from a minimum of 0.03 mg/L against P. vulgaris to a maximum of 1 mg/L against Enterobacter spp., and ertapenem was the most active drug tested in all cases. Imipenem also showed a good activity, with MIC90s ranging from 0.5 to 4 mg/L.
The highest MIC90s of imipenem were found with Enterobacter (2 mg/L) and Morganella (4 mg/L) species. Ertapenem always showed an MIC equal to or less than that of imipenem, except for four strains of Enterobacter cloacae, three E. coli strains and a single strain of K. pneumoniae, which yielded MICs one to two dilutions greater for ertapenem compared with imipenem.
None of the bacteria studied showed resistance to the tested carbapenems, and only nine strains of M. morganii showed intermediate susceptibility (MIC 4 mg/L) to imipenem.
Antibiotics routinely used to treat UTIs, such as co-trimoxazole, showed high resistance values, particularly against E. coli (92.4% resistance), P. mirabilis (88%) and P. vulgaris (60%). In contrast, Enterobacter spp. were highly susceptible, with a resistance rate of only 2.4%. Fosfomycin had an MIC90 > 128 mg/L for all groups tested, except for Enterobacter spp., where the MIC90 was 128 mg/L, and E. coli, where it was 8 mg/L.
On comparing antibiotic resistance among ESBL-producing strains of E. coli (n = 35) and E. coli strains not producing ESBLs (n = 280), statistically significant differences were obtained for ciprofloxacin (P = 0.002) and gentamicin (P = 0.011). As regards ertapenem, only a slight increase in MIC50 was noted, the value being 0.015 mg/L for bacteria not producing ESBLs and 0.03 mg/L for ESBL-producing bacteria.
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Discussion |
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In routine practice, urinary infection isolates are much more frequent in females than in males. However, of the total bacteria studied (n = 482), 40% were isolated from male urine. This high percentage is due to the selection of resistant bacteria, which are more often present in complicated UTIs, which are in turn more common among males.
All the strains were susceptible to ertapenem, imipenem and amikacin, and ertapenem was the most potent of all the tested antibiotics. This same conclusion has been reached in other susceptibility studies involving non-selected Enterobacteriaceae in Australia, Europe and the USA.7,8,12 None of the bacteria studied was resistant to ertapenem, and the highest MIC90 recorded was 1 mg/L, for Enterobacter spp.
In our experience, the MIC90 for ESBL-producing strains of E. coli compared with strains not producing ESBLs was only a double step higher for piperacillin/tazobactam, amikacin and ertapenem, but not for co-amoxiclav. However, the ESBL-producing strains were significantly more resistant to ciprofloxacin and to gentamicin than those that did not produce ESBLs. For ESBL-producing Klebsiella spp. and ertapenem, other authors have found the MIC90 to range from 0.016 to 0.12 mg/L.7
In view of its important antibiotic potency against antibiotic-resistant Enterobacteriaceae, ertapenem may constitute a good therapeutic alternative for urinary infections caused by these pathogens, particularly in the hospital setting, where these conditions are increasingly common.
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Acknowledgements |
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Footnotes |
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References |
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2
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Gill, C. J., Jackson, J. J., Gerckens, L. S. et al. (1998). In vivo activity and pharmacokinetic evaluation of a novel long-acting carbapenem antibiotic, MK-826 (L-749,345). Antimicrobial Agents and Chemotherapy 42, 19962001.
3 . Cunha, B. A. (2002). Ertapenem. A review of its microbiologic, pharmacokinetic and clinical aspects. Drugs of Today (Barcelona, Spain: 1998) 38, 195213.
4
.
Edwards, J. R. & Betts, M. J. (2000). Carbapenems: the pinnacle of the ß-lactam antibiotics or room for improvement? Journal of Antimicrobial Chemotherapy 45, 14.
5
.
Fuchs, P. C., Barry, A. L. & Brown S. D. (1999). In-vitro antimicrobial activity of a carbapenem, MK-0826 (L-749,345) and provisional interpretive criteria for disc tests. Journal of Antimicrobial Chemotherapy 43, 7036.
6
.
Kohler, J., Dorso, K. L., Young, K. et al. (1999). In vitro activities of the potent, broad-spectrum carbapenem MK-0826 (L-749,345) against broad-spectrum ß-lactamase and extended-spectrum ß-lactamase-producing Klebsiella pneumoniae and Escherichia coli clinical isolates. Antimicrobial Agents and Chemotherapy 43, 11706.
7
.
Livermore, D. M., Carter M. W., Bagel, S. et al. (2001). In vitro activities of ertapenem (MK-0826) against recent clinical bacteria collected in Europe and Australia. Antimicrobial Agents and Chemotherapy 45, 18607.
8
.
Fuchs, P. C., Barry, A. L. & Brown, S. D. (2001). In vitro activities of ertapenem (MK-0826) against clinical bacterial isolates from 11 North American medical centers. Antimicrobial Agents and Chemotherapy 45, 19158.
9
.
Tomera, K. M., Burdmann, E. A., Pamo Reyna, O. G. et al. (2002). Ertapenem versus ceftriaxone followed by appropriate oral therapy for treatment of complicated urinary tract infections in adults: results of a prospective, randomized, double-blind multicenter study. Antimicrobial Agents and Chemotherapy 46, 2895900.
10 . Jimenez-Cruz, F., Jasovich, A., Cajigas, J. et al. (2002). A prospective, multicenter, randomized, double-blind study comparing ertapenem and ceftriaxone followed by appropriate oral therapy for complicated urinary tract infections in adults. Urology 60, 1622.[CrossRef][ISI][Medline]
11 . National Committee for Clinical Laboratory Standards. (2003). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow AerobicallySixth Edition: Approved Standard M7-A6. NCCLS, Wayne, PA, USA.
12
.
Pelak, B. A., Citron, D. M., Motyl, M. et al. (2002). Comparative in vitro activities of ertapenem against bacterial pathogens from patients with acute pelvic infection. Journal of Antimicrobial Chemotherapy 50, 73541.