In vitro antibacterial activity and beta-lactamase stability of the new carbapenem SM-7338

The in vitro activity of the new carbapenem SM-7338 was tested in comparison with imipenem, ceftazidime, cefotaxime, flomoxef, cefuzonam and cefmetazole against 2850 clinical bacterial isolates. SM-7338 showed good activity against a broad spectrum of grampositive and gram-negative bacteria. SM-7338 was very active against gram-negative bacteria, inhibiting allEnterobacteriaceae, except 25 % ofSerratia marcescens isolates, at a concentration of 0.78 mg/l. SM-7338 inhibited the majority ofPseudomonas spp. at concentrations of 3.13 mg/l, its activity being twofold higher than that of imipenem. However, the activity of SM-7338 against gram-positive cocci was about one-fourth that of imipenem. Against anaerobes, SM-7338 also had the best activity of the -lactams tested. The compound was inactive against methicillin-resistant staphylococci,Enterococcus faecium, Xanthomonas maltophilia andFlavobacterium spp., as were the other -lactams. SM-7338 was quite stable in the presence of various types of -lactamase, but was hydrolyzed byXanthomonas maltophilia -lactamase, as was imipenem. This high degree of stability was responsible for the potent activity of SM-7388 against -lactamase-producing species such asEnterobacter cloacae, Citrobacter freundii andProteus vulgaris. SM-7338 also showed bactericidal activity against clinical isolates at the MIC or at concentrations slightly above the MIC.     

Comparative in vitro antibacterial activity of the new carbapenem meropenem (SM-7338)

The in vitro antimicrobial activity of the new carbapenem meropenem (SM-7338) was determined by an agar dilution method in comparison with imipenem, ticarcillin/calvulanic acid, ceftazidime and the fourth-generation cephalosporin cefepime (BMY 28142). Meropenem showed superior activity againstEnterobacteriaceae (MIC900.06 mg/l) and against non-fermentative gram-negative rods, with the exception ofXanthomonas maltophilia. Meropenem had excellent activity against beta-lactamase-producingHaemophilus influenzae andNeisseria gonorrhoeae, and against theBacteroides fragilis group. Imipenem was slightly more active then meropenem against gram-positive cocci especiallyEnterococcus faecalis.     

Comparative in vitro activity of biapenem,a new carbapenem antibiotic

Biapenem is a new carbapenem antibiotic with high stability to human renal dehydropeptidase I. Its in vitro activity was compared with that of imipenem, meropenem, ceftazidime, ceftriaxone, piperacillin and gentamicin against a total of 650 recent clinical isolates. MICs were determined by a standard agar dilution procedure and all isolates were tested at two inocula (10⁴ and 10⁶ cfu). Biapenem inhibited 90 % of isolates ofEscherichia coli, Klebsiella spp.,Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia stuartii, Enterobacter spp.,Citrobacter freundii, Serratia marcescens, Salmonella typhi, Shigella sonnei andYersinia enterocolitica at 2 mg/l and was as active as or two- to four-fold more active than imipenem against all these species, with the exception ofSerratia marcescens, against which imipenem was two-fold more active. Biapenem was two-fold more active than imipenem againstPseudomonas aeruginosa (MIC90 4 mg/l) and had activity similar to that of imipenem against theBacteroides fragilis group (MIC90 0.5 mg/l) but was two-fold less active than imipenem against methicillin-susceptibleStaphylococcus aureus (MIC90 0.06 mg/l) and was, like imipenem, inactive against methicillin-resistantStaphylococcus aureus.     

Comparative activity of meropenem (SM-7338) against major respiratory pathogens and amikacin-resistant nosocomial isolates

Meropenem, a new broad-spectrum carbapenem antibiotic, demonstrated excellent in vitro activity against major respiratory pathogens includingMoraxella catarrhalis, Haemophilus influenzae andStreptococcus pneumoniae. Minimal inhibitory concentrations of meropenem forMoraxella catarrhalis andHaemophilus influenzae isolates were frequently less than those of imipenem. For nosocomial amikacin-resistant gram-negative bacilli, meropenem had eightfold lower MIC90 values compared to imipenem against strains ofSerratia marcescens, Enterobacter cloacae andEscherichia coli; it was 32-fold more active than imipenem againstProteus mirabilis isolates. Activity was similar to that of imipenem againstPseudomonas aeruginosa isolates. Overall, meropenem showed excellent activity against common community-acquired pathogens as well as amikacin-resistant nosocomial pathogens.     

Activité du doripénème sur les bactéries anaérobies strictes

Aims of the study

This study examines the activity of doripenem, a new carbapenem compound compared with amoxicillin-clavulanic acid, piperacillin + tazobactam, imipenem, clindamycin and metronidazole against 316 anaerobes.

Methods

Inoculum preparation and agar dilution method were performed according to the CLSI method for anaerobes (M11A7).

Results

At a concentration of 4 μg/ml doripenem and imipenem (IMP) inhibited 122 (96 %) and 126 (99 %) strains of the Bacteroides fragilis group, respectively. In contrast, doripenem appeared more potent than IMP against Gram-positive anaerobes inhibiting at the same concentration of 4 μg/ml 145/145 strains (100 %) versus 115/145 for IMP (79.3 %). Against 316 anaerobic strains, the carbapenem doripenem had an MIC₅₀ of 0.25 μg/ml and an MIC₉₀ of 2 μg/ml. Results were similar to those for imipenem (MIC₅₀ of 0.125 μg/ml and MIC₉₀ of 4 μg/ml). If we consider the resistant breakpoints of the two carbapenems as defined by EUCAST, the resistance rate for doripenem (MIC > 4 μg/ml) 1.6 % is similar to that of imipenem (MIC > 8 μg/ml) 1.3 %.

Conclusion

Thus independently of the PK/PD parameters the two carbapenems demonstrated very close activity; doripenem was more potent on Gram-positive anaerobes and slightly less potent against Gram-negative anaerobes mainly the B. fragilis group. Further clinical studies are needed to assess its usefulness in patients.     

Comparative in vitro activity of the new oxacephem antibiotic,flomoxef (6315-S)

The in vitro activity of flomoxef (6315-S) was determined and compared to that of different cephalosporins against 787 clinical isolates of staphylococci,Enterobacteriaceae and anaerobes. Flomoxef is similar in activity to latamoxef and cefotaxime againstEnterobacteriaceae, slightly more active than cephalothin and cefamandole against oxacillin-sensitive strains ofStaphylococcus aureus and minimally less active than cefamandole against oxacillin-resistant strains. Flomoxef showed similar or better activity than latamoxef and cefoxitin against most of the anaerobic species of medical importance.     

In vitro activity of gatifloxacin, a new fluoroquinolone, against 204 anaerobes compared to seven other compounds

The activity of gatifloxacin, a new fluoroquinolone derivative, was compared with the activities of ciprofloxacin, levofloxacin, amoxicillin, amoxicillin–clavulanate, imipenem, clindamycin and metronidazole against 204 anaerobes isolated from clinical specimens, by MIC determination, using the reference agar dilution method. When determining the overall activity against anaerobes, the MIC_50/90 (mg/L) values were amoxicillin 16/>64, amoxicillin–clavulanate 0.125/1, imipenem 0.25/0.5, clindamycin 0.5/>256, metronidazole 1/8, ciprofloxacin 2/32, levofloxacin 1/8 and gatifloxacin 0.5/4. The broad in vitro spectrum of gatifloxacin is promising for the treatment of mixed anaerobic infections, especially those of the respiratory tract, ear, sinus, skin and soft tissues, and bite wounds. These data suggest that gatifloxacin may have a clinical role in the treatment of infections in which anaerobic pathogens are involved.     

Activity of doripenem against extended-spectrum β-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa isolates

The in vitro activity of doripenem was evaluated against a recent collection of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and Pseudomonas aeruginosa isolates (201 ESBL-producing Enterobacteriaceae [153 Escherichia coli and 48 Klebsiella pneumoniae] and 201 P. aeruginosa). Comparator agents included amikacin, tobramycin, ciprofloxacin, cefepime, cefotaxime, ceftazidime piperacillin-tazobactam, imipenem, and meropenem. Both doripenem and meropenem inhibited 100% of the ESBL-producing Enterobacteriaceae at ≤0.5 μg/mL. For these isolates, the MIC₉₀ of doripenem (0.12 μg/mL) was 4-fold lower than that of imipenem (0.5 μg/mL). Against P. aeruginosa, the MIC₉₀ of doripenem and meropenem was 2 μg/mL, 4-fold lower than that of imipenem (8 μg/mL). At an MIC of ≤2 μg/mL, doripenem, meropenem, and imipenem inhibited 90.5%, 89.6%, and 82.1% of P. aeruginosa isolates, respectively. Doripenem maintained activity against imipenem-nonsusceptible isolates of P. aeruginosa; at an MIC of ≤4 μg/mL, it inhibited 15 of the 25 isolates with MICs for imipenem of >4 μg/mL. Doripenem is active against ESBL-producing Enterobacteriaceae and P. aeruginosa isolates. Its activity is similar to that of meropenem and slightly better than that of imipenem. The results of this study suggest that doripenem could be an alternative therapeutic agent for infections caused by these organisms.     

Comparative in vitro activity of A-56268 (TE-031), a new macrolide antibiotic

The in vitro activity of A-56268 (TE-031) was determined by either standard agar dilution or macrobroth tube dilution and comapred with erythromycin and other antimicrobial agents against 329 clinical aerobic and anaerobic bacterial isolates. A-56268 showed good to excellent in vitro activity against methicillin-sensitiveStaphylococcus aureus,Neisseria meningitidis, and most anaerobes tested with the exception ofBacteroides fragilis isolates. A-56268 had relatively poor activity against coagulase-negative staphylococci and methicillin-resistantStaphylococcus aureus. Except forHaemo philus spp., the activity of A-56268 was similar to or more potent than erythromycin against all other isolates tested. A-56268 did not have significant bactericidal activity against any of the isolates examined.     

Local imipenem activity against Pseudomonas aeruginosa decreases in vivo in the presence of siliconized latex

Zinc eluted from siliconized latex (SL) increases resistance of Pseudomonas aeruginosa to imipenem in vitro. A foreign body peritonitis model was used to evaluate the activity of imipenem using SL or silicone (S) implants. No differences were observed in mortality, positive blood cultures and tissue bacterial counts between SL and S implants. Implant-associated counts, however, were significantly higher in the SL group. It is concluded that SL decreases the activity of imipenem against P. aeruginosa.     

In vitro activity of ceftriaxone combined with tazobactam against anaerobic bacteria

The in vitro activity of ceftriaxone combined with tazobactam against 190 strains of anaerobic bacteria was compared with that of amoxicillin with clavulanic acid, ampicillin with sulbactam, piperacillin alone and with tazobactam, cefoxitin, and imipenem, i.e. beta-lactam antibiotics established in the treatment of anaerobic infections. All anaerobes tested were susceptible to 32 mg/l ceftriaxone when tazobactam was added at fixed ratios (ceftriaxone to tazobactam) of 2:1 and 8:1 and at constant concentrations of 2,4 and 8 mg/l, respectively. When 4 mg/l tazobactam was added, the MICs of ceftriaxone for 83 of 94 strains of theBacteroides fragilis group were reduced by a factor of 8 to 512; for eight strains, this reduction was two to fourfold. Only the MICs of ceftriaxone for threeBacteroides fragilis strains were not influenced.     

Comparative in vitro activity of A-56268

The comparative in vitro activity of A-56268 was studied using 1,006 clinical isolates including streptococci, enterococci, staphylocci,Neisseria gonorrhoeae, Haemophilus influenzae and anaerobes. A-56268 showed activity comparable to that of erythromycin and was more active than josamycin and roxithromycin against erythromycin-sensitive aerobic and facultatively anaerobic gram-positive cocci. A-56268 was the most active macrolide againstClostridium spp. andNeisseria gonorrhoeae. Josamycin was more active than either A-56268 or erythromycin against the anaerobic gram-positive cocci and theBacteroides fragilis group. Staphylococci moderately resistant or resistant to erythromycin (MIC 3.12–50 mg/l) remained susceptible to josamycin but not the other macrolides.     

In vitro activity of the new quinolone BAY y 3118 against anaerobic bacteria

The in vitro activity of BAY y 3118 against anaerobic cocci,Propionibacterium acnes, Clostridium perfringens, Clostridium difficile, Bacteroides fragilis, otherBacteroides spp. and fusobacteria was determined by an agar dilution method. This activity was compared with that of ciprofloxacin, ofloxacin, piperacillin, cefoxitin, imipenem, clindamycin and metronidazole. BAY y 3118, imipenem, clindamycin and metronidazole were the most active agents tested. The in vitro activity of BAY y 3118 against anaerobic bacteria was superior to that of ciprofloxacin and ofloxacin.     

In vitro anti-anaerobic activity of the cephalosporin derivative RWJ 54428, compared to seven other compounds

Agar dilution MIC was used to test the activity of RWJ 54428, a new cephalosporin derivative, compared to imipenem, meropenem, ceftriaxone, piperacillin, piperacillin–tazobactam, clindamycin and metronidazole against 363 anaerobes isolated from clinical specimens. RWJ 54428 had low MICs against most β -lactamase-negative Gram-negative rods, and all Gram-positive strains except Clostridium difficile . Imipenem and meropenem had the lowest MICs (MIC₅₀s of 0.125 mg/L and MIC₉₀s of 1.0 mg/L). Piperacillin–tazobactam, clindamycin and metronidazole were active against most strains, and ceftriaxone was active mainly against β -lactamase-negative organisms.     

Antimicrobial activity of the new carbapenem biapenem compared to imipenem,meropenem and other broad-spectrum beta-lactam drugs

The in vitro activity of biapenem was compared to that of imipenem, meropenem and other broad-spectrum beta-lactams. A total of 716 isolates from recent cases of clinical septicemia and an additional 137 stock strains possessing known beta-lactamases or other well-characterized resistance mechanisms were tested. The minimal concentrations inhibiting 90 % of strains (MIC90) ofEnterobacteriaceae species were for biapenem 0.03 to 1 mg/l and for imipenem 0.25 to 2 mg/l. No member of theEnterobacteriaceae was found to be resistant to biapenem. Biapenem and meropenem were the most active drugs againstPseudomonas aeruginosa, with an MIC90 of 1 mg/l. Biapenem was more active than ceftazidime against most gram-negative and gram-positive bacteria tested. Biapenem was as potent as imipenem against anaerobic bacteria (includingBacteroides fragilis), with an MIC90 of 0.25 mg/l. High MICs of biapenem were demonstrated forXanthomonas maltophilia, oxacillin-resistantStaphylococcus spp. andEnterococcus spp. These species have demonstrated resistance to other carbapenems and to most of the newer cephalosporins. The results of this study, coupled with previously documented favorable qualities of biapenem, endorse further investigation of this broad-spectrum antibacterial agent for clinical use.     

Pharmacological profile of a novel,orally active leukotriene B4 antagonist,SM-15178

SM-15178, a new hydroxyacetophenone derivative, was evaluated to determine its antiinflammatory activity and antagonistic activity against leukotriene B₄ (LTB₄). SM-15178 inhibited [³H]LTB₄ binding to its receptors on human neutrophils (IC₅₀=0.30M). It inhibited LTB₄-induced chemotaxis of human neutrophils (IC₅₀ =0.72M) with little inhibitory effect against C5a or FMLP-induced chemotaxis at concentrations up to 30M. The compound alone did not cause human neutrophil chemotaxis at concentrations up to 10M. LTB₄-induced chemotaxis of mouse and rat neutrophils and guinea pig eosinophils was also inhibited by the compound, with IC₅₀ values of 0.55, 0.52, and 0.58 M, respectively. In an in vivo study, SM-15178, given orally, significantly prevented LTB₄-induced transient leukopenia. It also suppressed LTB₄-induced bronchoconstriction in the guinea pig almost completely when given orally at a dose of 40 mg/kg. Furthermore, orally given SM-15178 suppressed arachidonic acid-induced neutrophil infiltration in mouse ears and Arthus reaction-induced paw edema in the mouse in a dose-dependent manner. These results suggest that SM-15178 is a selective and orally active LTB₄ antagonist and that it might be effective for the treatment of some types of inflammatory diseases.     

In vitro activity of biapenem against beta-lactamase producingEnterobacteriaceae

The activity of biapenem was compared with that of imipenem and cefotaxime against 108 strains of -lactamase producingEnterobacteriaceae. Biapenem and imipenem were very active, inhibiting 90 % of the strains at a concentration of 0.5 µg/ml. Both carbapenems were very active against plasmidic -lactamase producers, with MIC90s below 1 µg/ml. However, the MIC90 of biapenem for cephalosporinase producers was 1 µg/ml. Against strains producing extended-spectrum -lactamases, biapenem exhibited better activity against TEM-type producers (MIC90 0.25 µg/ml) than against SHV-type producers (MIC90 0.5 µg/ml). Overall, the in vitro antibacterial activity of biapenem is similar to that of imipenem.     

In vitro activity of L-627 against anaerobic bacteria

The in vitro activity of L-627 against 370 anaerobic bacterial strains including anaerobic cocci,Propionibacterium acnes, Clostridium perfringens, Clostridium difficile, Bacteroides fragilis, otherBacteroides spp. and fusobacteria was determined by the agar dilution method. This activity was compared with that of piperacillin, cefoxitin, imipenem, meropenem, clindamycin, metronidazole and chloramphenicol. L-627, imipenem, meropenem, clindamycin, metronidazole and chloramphenicol were the most active agents tested. L-627 had in vitro activity similar to that of the other carbapenems tested.     

In vitro activity of DMG-mino and DMG-DM Dot,two new glycylcyclines,against anaerobic bacteria

The in vitro activity of DMG-Mino and DMG-DM Dot against 350 anaerobic bacterial strains including anaerobic cocci,Propionibacterium acnes, Clostridium perfringens, Clostridium difficile, Bacteroides fragilis, otherBacteroides species and fusobacteria was determined by the agar dilution method. Their activity was compared with that of minocycline, doxycycline, piperacillin, cefoxitin, imipenem, clindamycin and metronidazole. DMG-Mino and DMG-DM Dot and imipenem were the most active agents tested. DMG-Mino and DMG-DM Dot had in vitro activity superior to that of minocycline and doxycycline.     

In vitro activity of ertapenem against anaerobes isolated from the respiratory tract

Ertapenem is a novel parenteral carbapenem with a long serum half-life. Its spectrum of activity is similar to that of imipenem and meropenem against Gram-positive bacteria, Enterobacteriaceae and fastidious Gram-negative bacteria but it is less active against Pseudomonas aeruginosa and Acinetobacter spp. Several studies were performed in the United States but only one European study has shown that ertapenem has an excellent activity against anaerobes. The objectives of the present study were to test the activity of ertapenem against anaerobes isolated prospectively from the lower and upper respiratory tracts, and to compare their susceptibility with that of anaerobic isolates from other body sites. Fifty-three isolates from the respiratory tract, as well as 50 isolates from various other body sites were tested with E-tests against six antibiotics. For respiratory isolates and for isolates from other sites, MIC 90 values (mg/l) were, respectively, >32 and >32 for penicillin, 0.38 and 0.75 for amoxicillin/clavulanate, 48 and >256 for ceftriaxone, 0.12 and 0.75 for ertapenem, 12 and >256 for clindamycin and 2 and 12 for moxifloxacin. The higher susceptibility of respiratory tract isolates was mainly due to the different distribution of isolated species: only three respiratory isolates but 22 other isolates belonged to the Bacteroides fragilis group. This study confirms the excellent anti-anaerobic activity of ertapenem against anaerobic isolates from the respiratory tract.