MIC 90s Research Articles

In vitro activity evaluations of cefdinir (FK482, CI-983, and PD134393): A novel orally administered cephalosporin

Cefdinir, a so-called third-generation oral cephalosporin was tested in vitro against over 700 pathogens from patients with bacteremia. Cefdinir was very active against the Enterobacteriaceae with a 50% minimum inhibitory concentration (MIC 50) value range of ⩽0.03–8 μg/ml. The enteric species having the highest MIC 90s (⩾16 μg/ml) were Citrobacter freundii, and the enterobacters, Morganella morganii, Proteus vulgaris, and Serratia marcescens . Cefdinir was generally two- to fourfold less active than cefixime, but markedly more potent with a wider spectrum compared with older oral cephalosporins, cefaclor or cefuroxime. In contrast to cefixime, cefdinir inhibited Staphylococcus aureus (MIC 90, 1 μg/ml) and other staphylococci. Pneumococci, β-hemolytic streptococci, Haemophilus influenzae, Moraxella catarrhalis, and pathogenic Neisseria spp. (MIC 90s, 0.12–0.5 μg/ml) were cefdinir susceptible, but Pseudomonas aeruginosa, oxacillin-resistant staphylococci and Bacteroides fragilis gr. strains were resistant. Cefdinir was generally bactericidal with a minimal inoculum effect at 10 6 colony-forming units per spot. Cefdinir β-lactamase hydrolysis by some recently described extended broad spectrum β-lactamases was suspected. Cefdinir exhibited a wide, balanced spectrum for an oral cephalosporin indicating possible clinical use against susceptible pathogens in respiratory tract, urinary tract, genital and cutaneous infections.

In vitro activity of sparfloxacin (CI-978, AT-4140, and PD 131501): A quinolone with high activity against gram-positive bacteria

Sparfloxacin (CI-978, AT-4140 and PD 131501) is a new antimicrobial agent of the piperazinyl quinolone class. Relative to other quinolones, it is a potent antistaphylococcal and antistreptococcal drug in vitro: The microbroth 90% minimum inhibitory concentration (MIC 90) (in μg/ml) was 0.25 vs 26 methicillin-resistant and -sensitive coagulase-positive and - negative staphylococci and 20 Streptococcus pneumoniae; 0.5 vs 20 strains each of S. pyogenes, S. agalactiae, and Enterococcus faecalis. The data indicate sparfloxacin to be generally superior to ciprofloxacin, ofloxacin, oxacillin, cefazolin, doxycycline, amikacin, and vancomycin against these Gram-positive bacterial groups. Additional MIC 90s were determined for Haemophilus influenzae, Moraxella (Branhamella) catarrhalis, and Neisseria gonorrhoeae (≤ 0.03); Enterobacteriaceae (0.5); and Listeria monocytogenes (1). Activity was generally unchanged with light, 50% human serum, aerobic-anaerobic atmosphere, 5% sodium cholate, cation supplementation, and 100-fold increased or decreased inoculum; as with other quinolones, potency was measurably diminished with decreasing pH (pH ≤ 6.0) and in 100% urine. Naturally occurring resistant mutants occurred at frequencies of 10 −8 or lower.

In vitro antimicrobial activity of sparfloxacin (AT-4140, CI-978, PD 131501) compared with numerous other quinolone compounds

Sparfloxacin (AT-4140, CI-978, PD 131501) was tested against over 800 recent bacteremic strains and compared with ciprofloxacin and six other fluoroquinolones. The 90% minimum inhibitory concentration (MIC 90) ranges for the Enterobacteriaceae species were (a) sparfloxacin, 0.03–1 μg/ml and (b) ciprofloxacin, 0.015–0.25 μg/ml. Moraxella catarrhalis, Haemophilus influenzae, and Neisseria gonorrhoeae were very susceptible to sparfloxacin (MIC 90s, 0.004–⩽0.03 μg/ml) and the other comparison drugs. Staphylococcus aureas and other staphylococci were generally susceptible to the tested fluoroquinolones but very susceptible to sparfloxacin and WIN 57273. All β-hemolytic streptococci, enterococci, and pneumococci had sparfloxacin MICs of ⩽1 μg/ml. Sparfloxacin was quite active against anaerobic bacteria including Bacteroides fragilis gr. and Gram-positive strains (MIC 90s, ⩽2 μg/ml). The most resistant enteric bacilli were among Serratia marcescens and the Proteae, especially the Providencia spp. (two- to eightfold higher MICs). Pseudomonas aeruginosa strains were also susceptible to sparfloxacin (MIC 90, 2 μg/ml). Magnesium ions, CO 2 incubation, and low pH had some adverse effect on sparfloxacin MICs, and resistance development was documented among current clinical isolates of staphylococci, pseudomonas, and some enteric species.

Antimicrobial activity of E-1040, a novel thiadiazolyl cephalosporin compared with other parenteral cephems

E-1040, a new parenteral fourth-generation cephalosporin, was tested against > 600 bacteremic pathogens and compared with cefotaxime, ceftazidime, and cefpirome. E-1040 activity against Staphylococcus aureus was comparable (MIC 90, 8 μg/ml) to ceftazidime, but inferior to cefotaxime (MIC 90, 2 μg/ml) and cefpirome (MIC 90, 0.5 μg/ml). β-Hemolytic streptococci and most Gram-positive anaerobes were also susceptible to E-1040. Some strains of coagulase-negative staphylococci, all oxacillin-resistant Staphylcoccus spp., enterococci, and Bacteroides fragilis group strains were resistant to E-1040 (MIC 90, >64 μg/ml). Comparative tests for E-1040 and the three other cephalosporins against pseudomonads and nonenteric Gramnegative bacilli showed E-1040 to be generally most active. The E-1040 MIC 90 for Pseudomonas aeruginosa was 1 μg/ml and for ceftazidime it was 4 μg/ml. Haemophilus influenzae, Moraxella catarrhalis, and Neisseria spp. has E-1040 MIC 90s ranging from 0.12 to 2 μg/ml. Neisseria gonorrhoeae, strains resistant to penicillin, did not have markedly elevated E-1040 MICs compared with penicillin-susceptible strains. Enterobacteriaceae species had all MICs of ≤8 μg/ml for E-1040 and cefpirome, indicating activity against strains producing stably derepressed β-lactamases. E-1040 appeared to be β-lactamase stable, little influenced by testing systems or media, and was bactericidal. E-1040 seems to have promise as a parenteral β-lactam for use on strains resistant to “third-generation” cephalosporins and other families of drugs such as aminoglycosides and fluoroquinolones.

Antimicrobial activity of cefpirome an update compared to five third-generation cephalosporins against nearly 6000 recent clinical isolates from five medical centers

Cefpirome, cefotaxime, ceftazidime, cefoperazone, ceftizoxime, and ceftriaxone were tested against ∼6000 fresh clinical isolates from five medical centers. For 3031 strains of Enterobacteriaceae tested, cefpirome consistently had the lowest MIC 50s and lowest percentage of resistant strains. Cefpirome was also the most active agent against the 2138 Gram-positive cocci tested; Staphylococcus haemolyticus was uniformly resistant to all agents tested. Against 791 nonenteric Gram-negative bacilli, the activity of cefpirome was most comparable to that of cefoperazone and slightly less active than ceftazidime. Among the current third-generation cephalosporins, cefotaxime and cefoperazone emerged as having better overall balanced activity. Ceftazidime displayed poorest coverage against Enterobacteriaceae and Gram-positive organisms. Ceftizoxime also provided compromised coverage of staphylococci and nonenteric Gram-negative bacilli. Cefpirome remains as active as originally described in 1984 and possesses a slightly wider spectrum of activity against contemporary aerobic pathogens compared to currently marketed third-generation cephalosporins.

Evaluation of in vitro antimicrobial activity of lomefloxacin against staphylococci, enterococci, Enterobacteriaceae, and Pseudomonas aeruginosa

In vitro antimicrobial activity of lomefloxacin and other antibiotics (norfloxacin, β-lactams, cotrimoxazole, netilmicin, and miokamycin) was evaluated against 317 clinical isolates including Staphylococcus aureus, enterococci, Enterobacteriaceae, and Pseudomonas aeruginosa. Lomefloxacin showed a high in vitro activity against a wide variety of bacterial species. Against Enterobacteriaceae, lomefloxacin displayed the highest activity (MIC 90s, ⩽1 μg/ml), and it was usually more active than ampicillin and netilmicin, and often more active than cotrimoxazole. Lomefloxacin showed a good antimicrobial activity also against both methicillin-susceptible and methicillin-resistant S. aureus, as it was able to inhibit 90% of staphylococcal strains at a concentration ⩽2 μg/ml. Against enterococci and P. aeruginosa, lomefloxacin was usually less active (MIC 90s, 8 μg/ml). As compared to norfloxacin, lomefloxacin displayed an overall similar activity against staphylococci and enterococci, but appeared less active against Gram-negative bacteria. Bactericidal activity of lomefloxacin against E. coli, when assayed by a novel method, proved to be high, and results indicate that an oral dose of 200 mg of lomefloxacin should exert a very high bactericidal activity against E. coli in urinary tract infections, even in those sustained by large bacterial populations.

Comparative in vitro activity of lomefloxacin (SC 47111 or NY-198) against fresh clinical bacterial isolates

The in vitro antibacterial activity of a new difluorinated quinolone (lomefloxacin) was compared with that of ten selected antibiotics against 744 fresh bacterial isolates representing 32 species. Lomefloxacin was comparable to other quinolones tested against Enterobacteriaceae (MIC 90, ⩽0.25 μg/ml) and generally more effective than other compounds tested against Staphylococcus spp. and Pseudomonas aeruginosa with MIC 90s of ⩽2 and ⩽4 μg/ml, respectively.

Susceptibility of clinically important Bacteroides species against enoxacin-metronidazole and enoxacin-clindamycin combinations

To assess the activity of enoxacin, clindamycin and metronidazole, MICs of clinical isolates of saccharolytic intestinal Bacteroides spp. were determined, using the agar dilution method according to NCCLS guidelines. Checkerboard titrations of enoxacin-metronidazole and enoxacin-clindamycin were done on Wilkins-Chalgren agar; inoculation, incubation and reading of plates were as for determination of MICs. Metronidazole MIC 90s for Bacteroides fragilis (23 strains) and Bacteroides thetaiotaomicron (23 strains) were 0.5 mg/l, clindamycin MIC 90 for B. fragilis was 1 mg/l, and for B. thetaiotaomicron 8 mg/l, whereas enoxacin MIC 90 values were 16 mg/l and 64 mg/l, respectively. The evaluation of the inhibitory effects of the combination enoxacin-metronidazole for B. fragilis showed additional effects in eleven strains, indifference in seven strains and antagonism in one. The figures for B. thetaiotaomicron showed addition in five strains, indifference in 17 strains, antagonism in one. For B. fragilis the combination enoxacin-clindamycin showed addition in ten strains, indifference in six, and antagonism in one; for B. thetaiotaomicron synergism in one strain, addition in four strains, indifference in 17 strains. In conclusion, the absence of antagonism and the overall preponderance of additional and indifferent effects warrant the use of enoxacin in combination with metronidazole or clindamycin in clinical trials of treatment of anaerobic-aerobic mixed infections.

Cefotetan: A review of the microbiologic properties and antimicrobial spectrum

Cefotetan (formerly ICI 156834 and YM09330) is a 7-methoxy cephalosporin possessing some advantageous antimicrobial spectrum, safety, and pharmacokinetic characteristics compared with other so-called second-generation cephalosporins. The published literature was reviewed and the cefotetan quantitative susceptibility testing data from nearly 31,000 isolates was tabulated. Against 15,769 enteric bacilli, cefotetan was observed to have a potency and spectrum more closely resembling a third-generation cephalosporin and markedly superior to cefoxitin. The mean of all MIC 90s reported for the Enterobacteriaceae ranged from 0.06 to 13 micrograms/ml except for citrobacter species, E. cloacae, Enterobacter species, and C. freundii. The mean MIC 50 for all 22 recorded species was in the susceptible range. Cefotetan was very effective against B. catarrhalis, H. influenzae, and pathogenic Neisseria species. However, cefotetan and cefoxitin were not active against Pseudomonas species, Acinetobacter species, and some rarely isolated species. Cefotetan was moderately active against the staphylococci (mean MIC 50, 7.6 to 26 micrograms/ml) and streptococci (mean MIC 50, 0.9 to 6.6 micrograms/ml). The coagulase-negative staphylococcus species generally had higher cefotetan and cefoxitin minimum inhibitory concentrations compared with the S. aureus isolates. Oxacillin-resistant staphylococci were resistant to cefotetan. The enterococci, JK group diphtheroids, Corynebacterium species, and L. monocytogenes isolates were resistant. A review of 4,751 strict anaerobes showed cefotetan to have a very comparable activity and spectrum to cefoxitin. The 1,291 B. fragilis strains had a mean MIC 50 and MIC 90 of 5.4 and 23 micrograms/ml, respectively. These values were slightly superior to cefoxitin when tested in parallel. More elevated minimum inhibitory concentrations were observed for other B. fragilis group species for cefoxitin and cefotetan. The mean cefotetan MIC 90 for all other anaerobic bacteria except the Eubacterium species and Lactobacillus species predict favorable clinical efficacy. The beta-lactamase stability of cefotetan is very similar to that of other 7-methoxy cephalosporins. Cefotetan also inhibits Type Ia cephalosporinases with high enzyme affinity and is an inducer of these beta-lactamases, although cefotetan is not rapidly hydrolyzed. Synergy between cefotetan and numerous other antibiotics has been reported, but antagonism has also been occasionally observed.

Imipenem ( N-formimidoyl thienamycin): In vitro antimicrobial activity and β-lactamase stability

In vitro studies with imipenem (N-formimidoyl thienamycin or MK0787) were performed with 8481 clinical isolates in three separate medical centers. More extensive comparative studies were also performed with 605 representative isolates, comparing imipenem to six other β-lactams. Although the newer β-lactams were often more active against susceptible species, imipenem demonstrated the broadest spectrum of antibacterial activity, with MIC 90s ≤ 4.0 μg/ml for all species tested except Pseudomonas maltophilia and P. cepacia . Imipenem was very active against all streptococci and staphylococci, in contrast to the third-generation cephalosporins. There was no evidence of cross-resistance between imipenem and the cephalosporins or penicillins. Resistance to hydrolysis by seven β-lactamase preparations was documented for imipenem, cefotaxime, and moxalactam. Like many other β-lactams, imipenem inhibited the Type I β-lactamase produced by Enterobacter cloacae . Other β-lactamases from gramnegative bacilli were also inhibited by high concentrations of imipenem.

In vitro evaluation of HR810, a new wide-spectrum aminothiazolyl alpha-methoxyimino cephalosporin.

HR810 (Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.) is a new, cyclical-pyridinium cephalosporin that appeared superior to numerous comparison drugs against 658 strains of aerobic and facultative anaerobic bacteria. Seventeen Enterobacteriaceae spp. were tested by broth microdilution methods, and the 50% MICs (MIC50S) and 90% MICs (MIC90s) were 0.03 to 0.12 and 0.03 to 2.0 micrograms/ml, respectively. Only one strain had an MIC greater than 8.0 micrograms/ml (99.6% is considered susceptible). HR810 inhibited 98% of Pseudomonas aeruginosa isolates at less than or equal to 16 micrograms/ml, and the MIC90 for Acinetobacter spp. was 4.0 micrograms/ml. It was also very active against Pseudomonas spp. and Staphylococcus aureus (MIC90, 0.5 micrograms/ml) but marginally active against methicillin-resistant staphylococcal strains (MIC90, 16 micrograms/ml) and enterococcus (MIC90, 32 micrograms/ml). Non-enterococcal streptococci had MIC50s ranging from 0.008 micrograms/ml for Streptococcus pyogenes to 0.12 micrograms/ml for pneumococci. All MICs of HR810 against Haemophilus and Neisseria spp. were less than or equal to 0.03 micrograms/ml (MIC50, 0.002 to 0.008 micrograms/ml). HR810 poorly inhibited beta-lactamases and was very stable against 11 tested beta-lactamases of plasmid (TEM, OXA, SHV-1, and PSE) and chromosomal (K1, K14, P99) types.

Ceftazidime, a pseudomonas-active cephalosporin: in-vitro antimicrobial activity evaluation including recommendations for disc diffusion susceptibility tests

The in-vitro qualities of ceftazidime, as compared to other beta-lactams and three other antimicrobials (amikacin, gentamicin and chloramphenicol), were evaluated in a multilaboratory, multiphasic study in the United States. A total of 12,986 recent clinical isolates were tested by reference dilution methods in six medical centres over 45-60 days. Ceftazidime was superior to the comparison cephalosporin (cefamandole) and comparable in spectrum and activity to gentamicin against Enterobacteriaceae. Of 8038 enteric bacilli tested, over 98% had CTAZ MICs < or = 8 mg/l with a mode of < or = 0.12 mg/l. Only Citrobacter freundii and Enterobacter aerogenes had ceftazidime MIC(90S) in the resistant range ( > or =32 mg/l). Staphylococcus aureus strains were less susceptible to ceftazidime (mode MIC 8 mg/l) compared to cefamandole or gentamicin. Ceftazidime was more effective than cefamandole or gentamicin against the beta-haemolytic streptococci and the pneumococcus. More than 90% of Pseudomonas aeruginosa, most other Pseudomonas spp. and Acinetobacter spp. were inhibited by ceftazidime at concentrations of 8 mg/l. In other comparative studies ceftazidime was found remarkably similar in spectrum to cefotaxime, cefoperazone and moxalactam against the Enterobacteriaceae, staphylococci and Streptococcus spp. Enterobacter cloacae was the only enteric species having ceftazidime MIC90 >8 mg/l. Only cefsulodin (mode MIC 2 mg/l) and cefoperazone (mode MIC 4 mg/l) shared the ceftazidime activity against Ps. aeruginosa. Ceftazidime MIC(50S) for Neisseria gonorrhoeae and Haemophilus influenzae (including beta-lactamase producers) were 0.03-0.06 and 0.015 mg/l, respectively. Ceftazidime was found to be bactericidal against most strains at or one doubling dilution above the MIC, and was relatively unaffected by increasing inoculum concentration (some strain variations). It perfused readily into bacterial cells and was effective against the majority of strains resistant to currently available cephalosporins and aminoglycosides. beta-lactamases of Types I-V and Bacillus cereus failed to significantly hydrolyse ceftazidime. Ceftazidime inhibited only Type I Ent. cloacae beta-lactamase hydrolysis. Disc diffusion tests favour the use of a 30 microg ceftazidime disc for the methods described by the National Committee Clinical Laboratory Standards (NCCLS). Quality control data are presented. Tentative 30 microg disc interpretive criteria, based on susceptible MICs of < or =8 mg/l(> 17 mm) and resistant > or =32 mg/l ( < or =13 mm), resulted in < 1% (false resistance or false susceptible) interpretive error rates. Staph. aureus was the species most commonly found to have strains with indeterminate ceftazidime zones or MICs. We found ceftazidime to possess one of the widest clinically usable antimicrobial spectrum by in-vitro testing of any beta-lactam tested and to be most comparable to broad-spectrum aminoglycosides such as amikacin, gentamicin and tobramycin.