Sezione di Microbiologia del Di.S.C.A.T., University of Genoa, Largo R.Benzi 10, 16132 Genoa, Italy
Received 14 May 2004; returned 4 July 2004; revised 31 August 2004; accepted 3 September 2004
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Abstract |
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Methods: MIC determinations and timekill curves were carried out following the procedures suggested by the NCCLS.
Results: According to NCCLS susceptibility breakpoints, ertapenem was comparable to the most potent compounds tested for all pathogens studied. Ertapenem was 100% active against penicillin-susceptible and -intermediate S. pneumoniae and against 60% of penicillin-resistant strains. Timekill tests at 4x MIC confirmed a pronounced bactericidal potency of ertapenem against these organisms. Interactions of ertapenem with several other agents against pneumococci resulted in clear synergic interactions (98.4%). Indifference was extremely rare and antagonism was not observed. All S. pyogenes strains tested were inhibited by ertapenem, irrespective of their macrolide resistance phenotypes. Ertapenem was also fully active against H. influenzae (100% susceptible) and M. catarrhalis (MIC90 0.0150.03 mg/L) even when capable of synthesizing ß-lactamases. Methicillin-susceptible S. aureus and K. pneumoniae, including extended-spectrum ß-lactamase-producing strains, were 100% susceptible to ertapenem.
Conclusions: Our results indicate that ertapenem has a suitable spectrum of activity against organisms encountered in community-acquired bacterial respiratory tract infections.
Keywords: carbapenems , timekill , interactions , bactericidal activity , Streptococcus pneumoniae
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Introduction |
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This study was designed to assess the activity of ertapenem, a new parenteral non-antipseudomonal carbapenem, against a large collection of recently isolated respiratory pathogens (550 strains). In addition, bactericidal activity of ertapenem against Streptococcus pneumoniae was determined by timekill curve experiments. Similarly, the outcome of combining ertapenem with several other antimicrobial agents commonly employed for antipneumococcal therapy was determined.
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Materials and methods |
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Ertapenem was provided by Merck Sharp and Dohme (Rome, Italy). The comparator molecules were obtained from commercial sources (SigmaAldrich, Milan, Italy) or from their respective manufacturers.
MICs of ertapenem and of the other antimicrobial agents tested were determined using the microdilution method and interpreted according to the breakpoints suggested by the National Committee for Clinical Laboratory Standards.4
The antibacterial activity of ertapenem against pneumococci was assessed by carrying out timekill curves following the NCCLS (1999) recommendations.5 Ertapenem (at a concentration corresponding to four times the MIC) was tested against 15 isolates of S. pneumoniae, characterized by the following phenotypes: three penicillin-susceptible (and susceptible to erythromycin, tetracycline, co-trimoxazole and chloramphenicol), three penicillin-intermediate (and susceptible to erythromycin, tetracycline, co-trimoxazole and/or chloramphenicol), three penicillin-resistant (and susceptible to erythromycin, tetracycline, co-trimoxazole and chloramphenicol), three erythromycin-resistant (and susceptible to penicillin, co-trimoxazole and chloramphenicol) and three multi-resistant strains (simultaneously penicillin-, co-trimoxazole- and chloramphenicol-resistant). Timekill tests to determine the activity of ertapenem combined with other agents (vancomycin, clarithromycin, rifampicin and levofloxacin), at half their respective MIC against the same S. pneumoniae isolates detailed above, were carried out as described by the NCCLS.5
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Results |
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Timekill curves at 4x MIC showed that after 6 h, ertapenem behaved as a bacteriostatic agent (9099% killing) against 15 S. pneumoniae strains irrespective of their resistance traits. However, prolonged incubation gave rise to a consistent bactericidal activity against all S. pneumoniae strains, with 99.9% killing after 24 h of exposure (Figure 1).
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Against erythromycin-susceptible S. pyogenes strains, ertapenem was the most potent agent tested together with other ß-lactams, levofloxacin, vancomycin, chloramphenicol and macrolides (100% susceptible strains), followed by tetracycline (87.5%). Similar results were obtained, macrolides excluded, for erythromycin-resistant strains, irrespective of the mechanism of resistance.
All antimicrobial agents studied, with the exception of ampicillin for ß-lactamase-producing strains, were highly active, in terms of MIC90, against M. catarrhalis. Ertapenem, meropenem, co-amoxiclav and rifampicin showed the lowest MIC90 for ß-lactamase-negative M. catarrhalis (0.015 mg/L), while against the ß-lactamase-positive organisms the MIC90 of ertapenem was two-fold higher (0.03 mg/L).
All ß-lactamase-negative H. influenzae isolates were susceptible to ertapenem, other ß-lactams, quinolones, azithromycin and rifampicin, whereas 96% of these isolates were susceptible to tetracycline, 88% to clarithromycin and co-trimoxazole and 86% to chloramphenicol. On the other hand, 100% of ß-lactamase-positive ampicillin-resistant strains were susceptible to ertapenem and all other antibiotics, excluding tetracycline (80%) and co-trimoxazole (90%).
Against methicillin-susceptible S. aureus, ertapenem, imipenem, the cephalosporins, co-amoxiclav, vancomycin and levofloxacin were active against 100% of the isolates followed by ciprofloxacin (99%), rifampicin (99%), chloramphenicol (98%), amikacin (98%), tetracycline (97%), co-trimoxazole (96%), gentamicin (91%), clindamycin (71%), clarithromycin (69%), azithromycin (69%), ampicillin (18%) and penicillin (18%).
Ertapenem was active against all K. pneumoniae, including ESBL-producers. With respect to these last microorganisms, ertapenem, imipenem, meropenem, co-amoxiclav and amikacin activity (all strains susceptible) exceeded that of tetracycline (80%), ciprofloxacin (30%) and co-trimoxazole (30%) and, as expected, extended-spectrum parenteral cephalosporins (0%).
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Discussion |
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Ertapenem, like other carbapenems, is efficacious against methicillin-susceptible staphylococci, but remains inactive against methicillin-resistant strains. Contrary to imipenem, ertapenem was fully active not only against penicillin-susceptible but also penicillin-intermediate S. pneumoniae. Ertapenem MIC90s were two-fold higher than those of imipenem, but in terms of percentage of susceptible strains, ertapenem is consistently more active than imipenem against pneumococci fully refractory to penicillin (60% versus 46.6%). On the contrary, ertapenem showed MIC90 values lower than those of cefotaxime and ceftriaxone, but since the NCCLS interpretative guidelines for non-meningeal isolates were adopted in this paper, the percentages of strains classified as susceptible (73.3% and 70.0%), rendered the third-generation injectable cephalosporins the most active ß-lactam agents tested. On the other hand, recent results from clinical trials with ertapenem versus ceftriaxone for the treatment of pneumococcal pneumonia, although on a limited number of patients, showed comparable clinical and bacteriological responses even for organisms for which penicillin MICs were 2 mg/L.9
A further confirmation of the good antipneumococcal activity of ertapenem has been provided here through the killing kinetics approach. Ertapenem was bactericidal against all pneumococci studied, irrespective of their penicillin or macrolide susceptibility phenotypes. The killing rates of ertapenem at 4x MIC were similar to those observed by other authors at 2x MIC.8 Increasing ertapenem concentrations did not therefore significantly influence the extent of killing, as expected due to ß-lactam general pharmacodynamics.
Given its characteristics, ertapenem has been approved in combination with a macrolide for initial empirical therapy of suspected community-acquired bacterial pneumonia in immunocompetent hospitalized adults.2 The fact that synergy often occurs when ertapenem interacts with other agents (clarithromycin, levofloxacin, rifampicin and vancomycin) suggested for the treatment of community-acquired pneumonia2 (CAP) even against penicillin-resistant pneumococci is a new finding, supporting its recent approval for such usage.
Although, at present, ertapenem has been licensed only for CAP, it can be predicted that its usage might be extended to other respiratory infections such as severe acute exacerbation of chronic bronchitis because of its appropriate spectrum.
Another potential role of ertapenem, as suggested by other authors, is in outpatient therapy.6 This last therapeutic approach could be of particular interest in Italy, a country where third-generation injectable cephalosporins have been vastly employed. In view of this peculiar situation, it has been speculated that the relatively low prevalence of resistant S. pneumoniae circulating in our country during the 1990s might have been related, at least in part, to aggressive intramuscular therapy.10 This hypothesis is supported by the recent increase in overall S. pneumoniae resistance in our country concomitant to governmental directions that limit the prescription of third-generation injectable cephalosporins in the community.
Outpatient intravenous therapy because of its clear pharmacokinetic advantages over the intramuscular route, may thus represent, if correctly and judiciously adopted, a new strategy in the struggle to achieve higher clinical success and eradication rates as well as providing the pharmacoeconomic advantages that stem from avoiding the costs of hospitalization.
Since the widespread use of carbapenems may promote the dissemination of resistant strains, it is mandatory to stress that prudent prescribing practices will be fundamental in maintaining the clinical utility of these last resort antimicrobial agents.
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Acknowledgements |
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Footnotes |
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References |
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2 . Mandell, L. A., Bartlett, J. G., Dowell, S. F. et al. (2003). Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clinical Infectious Diseases 37, 140533.[CrossRef][ISI][Medline]
3 . Felmingham, D. (2002). Evolving resistance patterns in community-acquired respiratory tract pathogens: first results from the PROTEKT global surveillance study. Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin. Journal of Infection 44, Suppl. A, 310.[ISI][Medline]
4 . National Committee for Clinical Laboratory Standards. (2004). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow AerobicallySixth Edition: Approved Standard M7-A6 and M100-S14. NCCLS, Wayne, PA, USA.
5 . National Committee for Clinical Laboratory Standards. (1999). Methods for Determining Bactericidal Activity of Antimicrobial Agents: Approved Guideline M26-A. NCCLS, Wayne, PA, USA.
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Ortiz-Ruiz, G., Vetter, N., Isaacs, R. et al. (2004). Ertapenem versus ceftriaxone for the treatment of community-acquired pneumonia in adults: combined analysis of two multicentre randomized, double-blind studies. Journal of Antimicrobial Chemotherapy 53, Suppl. S2, ii5966.
10 . Marchese, A., Mannelli, S., Tonoli, E. et al. (2001). Prevalence of antimicrobial resistance in Streptococcus pneumoniae circulating in Italy: results of the Italian Epidemiological Observatory Survey (19971999). Microbial Drug Resistance 7, 27787.[CrossRef][ISI][Medline]