a Department of Pathology (Clinical Microbiology), Hershey Medical Center, 500 University Drive, Hershey, PA 17033 b Case Western Reserve University, Cleveland, OH 44106, USA
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Abstract |
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Introduction |
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MEN 10700 is a new alkylamino penem with a sarcosinamido group at position 2.2,3 Previous reports have documented the broad-spectrum activity of this compound against a wide variety of aerobic and anaerobic Gram-positive and -negative organisms, including pneumococci.2,3 This study expands the latter findings by testing (i) the activity of MEN 10700, compared with amoxycillin, co-amoxiclav, cefotaxime, cefepime, imipenem, meropenem, ciprofloxacin, clarithromycin and vancomycin against 202 penicillin susceptible and resistant pneumococci by agar dilution; (ii) the activity of the same compounds against 12 penicillin susceptible and resistant pneumococci by timekill kinetics.
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Materials and methods |
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Two hundred and two pneumococcal isolates were studied by agar dilution, and comprised
57 penicillin-susceptible (MIC 0.06 mg/L), 84 -intermediate (MIC 0.1251.0 mg/L)
and 61 -resistant (MICs
2.0 mg/L) isolates. For timekill kinetics, four each of
penicillin-susceptible, -intermediate and -resistant isolates were studied. MEN 10700 was
obtained from Menarini Ricerche, S.p.A. (Florence, Italy). Other compounds were obtained from
their respective manufacturers.
MIC method
Agar dilution for the 202 isolates was performed in air as described previously by our group1 using MuellerHinton agar (BBL) with 5% added sheep blood and inocula of 1 x 104 cfu/spot. NCCLS does not recommend agar dilution for routine pneumococcal susceptibility testing. Broth MICs for the 12 isolates tested by timekill were determined, according to NCCLS recommendations, in MuellerHinton broth with 5% added lysed horse blood and inocula of 1 x 105 cfu/mL.4 Clavulanate was added to amoxycillin at a fixed ratio of 1:2. Standard quality control isolates4 were included in each run of agar and broth dilution MICs. Because isolates tested were stock isolates which had been subcultured many times, CO2 was not needed for adequate growth.
Timekill testing
Tubes containing 5 mL cation-adjusted MuellerHinton broth + 5% lysed horse blood with doubling antibiotic concentrations were inoculated with 5 x 105 to 5 x 106 cfu/mL and incubated at 35°C in a shaking water bath. The original inoculum was determined by using the untreated growth control. Viability counts of antibiotic-containing suspensions were performed at 0, 3, 6, 12 and 24 h, by plating dilutions onto 5% sheep blood agar plates. The lower limit of sensitivity of colony counts was 300 cfu/mL.4
Timekills were analysed by determining the number of isolates yielding a difference in log10 cfu/mL of 1, 2 and 3 at 0, 3, 6, 12 and 24 h, compared with counts at time 0 h. Antimicrobials were considered bactericidal at the lowest concentration that reduced the original inoculum by >3 log10 cfu/mL (99.9%) at each of the time periods, and bacteriostatic if the inoculum was reduced by 03 log10 cfu/mL. With sensitivity threshold and inocula used in these studies, no problems were encountered in delineating 99.9% killing, when present. Bacterial carryover was addressed by dilution as described previously.4
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Results |
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Discussion |
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MEN 10700 is another recently described novel broad-spectrum penem.2,3 In a recent study,3 MEN 10700 was found to be most active against staphylococci and streptococci, slightly less active against Escherichia coli, Klebsiella pneumoniae, Enterobacterspp., Citrobacter spp., Moraxella catarrhalis and peptostreptococci, moderately active against Enterococcus faecalis, Proteus spp., Serratia marcescens, Acinetobacter spp., Clostridium and Bacteroides spp., and inactive against Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Enterococcus faecium.In another study, Fontana and co-workers2 found that the antibacterial spectrum of MEN 10700 was slightly narrower than that of imipenem, but compared favourably with those of ritipenem and cefotaxime. In preliminary studies included in the latter two papers,2,3 MIC50/MIC90 values of MEN 10700 were 0.0150.03/0.030.06 and 0.5/1.0 mg/L against penicillin-susceptible and -resistant isolates, respectively. However, the penicillin MICs for the latter group were not given. Bactericidal activity was demonstrated by the replica plating method.
In our study, MEN 10700 was found to have MICs comparable with those of amoxycillin, co-amoxiclav, cefotaxime, cefepime and meropenem.1 Imipenem had the lowest MICs of all ß-lactams tested, but the epileptogenic potential of this compound1 precludes its use in serious systemic pneumococcal infections. Meropenem seems to lack this side-effect and may be used for treatment of these infections. Choice between meropenem and a penem such as MEN 10700 should be made upon the basis of MICs in combination with pharmacokinetic and pharmacodynamic studies (not yet available for MEN 10700).
Kill kinetics of MEN 10700 were similar to those of all other ß-lactams studied, relative to MICs. Because MICs of ciprofloxacin cluster around the breakpoint, it is not recommended for treatment of serious pneumococcal infections.1 Slow kill kinetics of macrolides against pneumococci, as well as higher macrolide MICs in pneumococci with raised penicillin MICs, have been described.4
If results of toxicological and pharmacokinetic studies show promise, this study indicates that MEN 10700 shows potential for treatment of infections caused by penicillin-susceptible and -resistant pneumococci.
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Acknowledgments |
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Notes |
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References |
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2 . Altamura, M., Perrotta, E., Sbraci, P., Pestellini, V., Arcamone, F., Cascio, G. et al. (1995). 2-Substituted penems with amino acid-related side chains: synthesis and antibacterial activity of a new series of ß-lactam antibiotics. Journal of Medical Chemistry 38, 424456.
3 . Hamilton-Miller, J. M. T. & Shah, S. (1997). In-vitro microbiological assessment of a new penem, MEN 10700. Journal of Antimicrobial Chemotherapy 39, 57584.[Abstract]
4 . Pankuch, G. A., Lichtenberger, C., Jacobs, M. R. & Appelbaum, P. C. (1996). Antipneumococcal activities of RP 59500 (quinupristin/dalfopristin), penicillin G, erythromycin and sparfloxacin determined by MIC and rapid timekill methodologies. Antimicrobial Agents and Chemotherapy 40, 16536.[Abstract]
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9 . Utsui, Y., Takenouchi, T., Masuda, N., Domon, H., Kakuta, M., Ishii, C. et al. (1996). CS-834, a new oral carbapenem: II. In vitro evaluation of R-95867, the active metabolite of CS-834. In Program and Abstracts of the Thirty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, 1996. Abstract F106, p. 118. American Society for Microbiology, Washington, DC.
10 . Wise, R., Andrews, J. M. & Danks, G. (1983). Comparison of in vitro activity of FCE 22101, a new penem, with those of other ß-lactam antibiotics. Antimicrobial Agents and Chemotherapy 24, 90914.[ISI][Medline]
Received 12 November 1998; returned 10 February 1999; revised 24 February 1999; accepted 6 April 1999