Comparative In Vitro Activity of Five Cephalosporin Antibiotics Against Salmonellae

The in vitro activities of five cephalosporin antibiotics against 121 strains of salmonellae were compared. Cefamandole and cefaclor were more potent than cefazolin, and these three drugs were more active than cephalothin and cephalexin.     

HR 756, a New Cephalosporin Active Against Gram-Positive and Gram-Negative Aerobic and Anaerobic Bacteria

The in vitro activity of HR 756, 7-[2-(2-amino-4-thiazolyl)-2-(Z)-(methoximino)acetamido] cephalosporanic acid, was investigated against 659 isolates. HR 756 inhibited Neisseria and Haemophilus species at concentrations similar to those needed with ampicillin. It inhibited beta-lactamase-producing N. gonorrhoeae and H. influenzae. HR 756 was the most active compound tested against members of the Enterobacteriaceae, inhibiting most isolates of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella, Enterobacter, and Shigella at concentrations of less than 0.1 mug/ml. It was twice as active as carbenicillin against Pseudomonas aeruginosa and inhibited Bacteroides fragilis as well as cefoxitin. HR 756 killed E. coli, Staphylococcus aureus, and P. aeruginosa at rates similar to other beta-lactam antibiotics.     

Activity of Four Cephalosporin Antibiotics In Vitro Against Bovine Udder Pathogens and Pathogenic Bacteria Isolated from Newborn Calves

The in vitro activity of chephaloridine, cephalexin, cefatrizine (BL-S640), and cephapirin (BL-P-1322) was evaluated by the serial dilution method against pathogenic gram-positive and gram-negative bacteria isolated from bovine udders and neonatal calf diseases. Cephapirin showed the comparatively greatest activity against the most common streptococcal species associated with bovine mastitis, whereas cephaloridine exhibited the best activity against Staphylococcus aureus. Cefatrizine was more active than the other cephalosporins against the gram-negative bacteria studied. In general, the minimal bactericidal concentration of each cephalosporin was two- to fourfold lower than the comparative value reported in the literature against the same type of pathogen of human origin.     

Activity of Five Aminoglycoside Antibiotics In Vitro Against Gram-Negative Bacilli and Staphylococcus aureus

The in vitro susceptibility to BB-K8, butirosin, gentamicin, sisomicin, and tobramycin of seven groups of clinically significant gram-negative bacilli and Staphylococcus aureus was assessed by using the International Collaborative Study-World Health Organization criteria. The activity of gentamicin, sisomicin, and tobramycin generally paralleled each other. Sisomicin was the most potent compound by weight and usually demonstrated the most rapid rate of killing. BB-K8 and butirosin were less potent, but higher serum levels may be achieved with these agents. BB-K8 generally showed the greatest ratio between achieveable mean peak serum levels and concentrations needed to inhibit [Formula: see text] of each group of organisms tested. Additionally, BB-K8 was active against six of seven highly gentamicin-resistant strains. All of these antibiotics showed diminished activity at pH 6.4 but only gentamicin and sisomicin showed occasionally enhanced activity at pH 8.4.     

In Vitro Activities of Membrane-Active Peptides against Gram-Positive and Gram-Negative Aerobic Bacteria

Four peptides, cecropin P1, magainin II, indolicidin, and ranalexin, were evaluated against 202 clinical isolates of gram-positive and gram-negative aerobic bacteria by a microbroth dilution method. The gram-negative isolates were more susceptible to cecropin P1. Ranalexin was the most active compound against the gram-positive strains. The bactericidal activity of each peptide was equivalent to, or 1 dilution above, the MIC. In conclusion, the four peptides exhibited different in vitro activities and rapid time-dependent killing.     

In Vitro Activity of 5-Episisomicin in Bacteria Resistant to Other Aminoglycoside Antibiotics

Eighty-seven isolates of Pseudomonas, Enterobacteriaceae, and Staphylococcus, chosen because of their resistance to other aminoglycosides, were tested for susceptibility to 5-episisomicin. Tests were performed in Mueller-Hinton agar and also, with 38 of these isolates, in Mueller-Hinton broth. Of Enterobacteriaceae, 85 and 95.5% were inhibited by 5 and 10 mug of 5-episisomicin per ml, respectively. Amikacin inhibited 74 and 91% of the strains at 10 and 20 mug/ml, respectively. Fifty-four percent of P. aeruginosa were inhibited by 5-episisomicin and amikacin. Eighty-three percent of S. aureus were inhibited by netilmicin and amikacin, whereas only 50% were inhibited by 5-episisomicin. Isolates resistant to 5-episisomicin were most often resistant to the other aminoglycosides and occurred in gram-negative bacilli that did not carry aminoglycoside-modifying enzymes. Five of 23 isolates that carried a 6'-N-acetyltransferase (AAC-6') and one of two that carried an aminoglycoside 3-acetyltransferase were resistant to and acetylate 5-episisomicin. Strains carrying other aminoglycoside-modifying enzymes were inhibited by 5-episisomicin. Thus, 5-episisomicin is a promising aminoglycoside not attacked by most aminoglycoside-modifying enzymes. Resistance will probably most often be based upon nonenzymatic mechanisms which will also affect other aminoglycosides.     

Comparative In Vitro Activity of New Beta-Lactam Antibiotics Against Anaerobic Bacteria

Several new beta-lactam antimicrobial agents have been introduced in the last few years. In this investigation, the in vitro activities of several recently introduced cephalosporins (cefoperazone, cefotaxime, ceftazidime, and ceftizoxime), moxalactam, and N-formimidoyl thienamycin were compared with those of cefoxitin, clindamycin, and metronidazole against 203 strains of anaerobic bacteria. At achievable serum levels, all of the antimicrobial agents were active against essentially 100% of the strains of anaerobic gram-positive cocci, Clostridium perfringens, Leptotrichia buccalis, and species of Selenomonas, Veillonella, and Eubacterium. Clindamycin, metronidazole, and N-formimidoyl thienamycin were the most active agents against the Bacteroides fragilis group, inhibiting all strains at concentrations which can be achieved in serum. Of the remaining agents tested against the B. fragilis group, cefoxitin (which required 64 μg/ml to inhibit 90% of the strains) was the most active, followed by cefoperazone (128 μg/ml), cefotaxime (128 μg/ml), moxalactam (128 μg/ml), ceftizoxime (256 μg/ml), and ceftazidime (>256 μg/ml). Important differences in cephalosporin susceptibility among species of the B. fragilis group were observed. Metronidazole and N-formimidoyl thienamycin were the most active drugs against species of clostridia other than C. perfringens; the other antibiotics displayed poor activity, although this is partly due to inclusion of a relatively large number of strains of Clostridium difficile which were very resistant to several of the cephalosporins. Only metronidazole was active against all species of Fusobacterium. Clindamycin and N-formimidoyl thienamycin displayed excellent activity against gram-positive, non-spore-forming bacilli, requiring ≤8 μg/ml to inhibit 100% of the strains. Ceftazidime, cefoperazone, and moxalactam were bactericidal for 25 strains of B. fragilis at concentrations equal or close to those required for inhibition. On the basis of its activity in vitro, N-formimidoyl thienamycin appears to be the most promising of the new beta-lactam antibiotics for the treatment of infections involving anaerobic bacteria.     

In Vitro Pharmacodynamic Studies of L-749,345 in Comparison with Imipenem and Ceftriaxone against Gram-Positive and Gram-Negative Bacteria

L-749,345 is a new parenteral carbapenem with a very long half-life similar to that of ceftriaxone. The aim of the present study was to investigate different pharmacodynamic parameters of L-749,345 in comparison with those of ceftriaxone and imipenem. The following studies were performed: (i) comparative studies of the MICs of L-749,345, imipenem, and ceftriaxone for 70 strains of gram-positive and gram-negative bacteria; (ii) comparative studies of the rate of killing of gram-positive and gram-negative bacteria by L-749,345, imipenem, and ceftriaxone; (iii) studies of the postantibiotic effects of L-749,345, imipenem, and ceftriaxone; and (iv) studies of the postantibiotic sub-MIC effects of L-749,345, imipenem, and ceftriaxone. Significantly lower MICs of L-749,345 compared with those of ceftriaxone were found for all gram-negative organisms except Haemophilus influenzae. The MICs of L-749,345 were similar to those of imipenem for all organisms except Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus, for which the MICs of L-749,345 were higher. A concentration-dependent killing of methicillin-resistant S. aureus but not methicillin-susceptible strains was noted for both L-749,345 and imipenem. All three of the investigated drugs exhibited a postantibiotic effect against the gram-positive strains but exhibited no postantibiotic effect against the gram-negative strains.     

In Vitro Activity of Josamycin Against Aerobic Gram-Positive Cocci and Anaerobes

Josamycin, a new macrolide antibiotic, was compared with ampicillin, erythromycin, and clindamycin in vitro against 25 isolates each of pneumococci, enterococci, Staphylococcus aureus, S. epidermidis, and nonenterococcal hemolytic streptococci and against 25 anaerobes including 10 Bacteroides fragilis. Minimal inhibitory concentration and minimal bactericidal concentration data were obtained for the aerobic organisms, using serial twofold tube dilutions in Mueller-Hinton broth. Minimal inhibitory concentrations were determined for the anaerobes by the agar dilution technique. Josamycin was comparable to erythromycin and clindamycin in activity against the pneumococci, streptococci, and staphylococci and was more active than clindamycin against enterococci. It was somewhat less active than ampicillin against enterococci and S. epidermidis and showed its greatest in vitro activity against anaerobes, being comparable to clindamycin.     

In Vitro Activity of Ozenoxacin against Quinolone-Susceptible and Quinolone-Resistant Gram-Positive Bacteria

In vitro activity of ozenoxacin, a novel nonfluorinated topical (L. D. Saravolatz and J. Leggett, Clin. Infect. Dis. 37:1210–1215, 2003) quinolone, was compared with the activities of other quinolones against well-characterized quinolone-susceptible and quinolone-resistant Gram-positive bacteria. Ozenoxacin was 3-fold to 321-fold more active than other quinolones. Ozenoxacin could represent a first-in-class nonfluorinated quinolone for the topical treatment of a broad range of dermatological infections.     

Comparative In Vitro Activity Profiles of Novel Bis-Indole Antibacterials against Gram-Positive and Gram-Negative Clinical Isolates

Antimicrobial susceptibilities of 233 Gram-positive and 180 Gram-negative strains to two novel bis-indoles were evaluated. Both compounds were potent inhibitors of Gram-positive bacteria, with MIC₉₀ values of 0.004 to 0.5 μg/ml. One bis-indole, MBX 1162, exhibited potent activity against all Gram-negative strains, with MIC₉₀ values of 0.12 to 4 μg/ml, even against high-level-resistant pathogens, and compared favorably to all comparator antibiotics. The bis-indole compounds show promise for the treatment of multidrug-resistant clinical pathogens.Antibiotic resistance is reaching a crisis level because few options remain to treat certain pathogenic bacteria—mainly those causing hospital-acquired infection, but with the potential to occur in the community (8) and on the battlefield (2). Of special note are the following particularly problematic pathogens: multidrug-resistant (MDR) Acinetobacter baumannii, extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella species, Pseudomonas aeruginosa, vancomycin-resistant enterococci (VRE [Enterococcus faecium]), methicillin-resistant Staphylococcus aureus (MRSA), and coagulase-negative staphylococci such as methicillin-resistant Staphylococcus epidermidis (MRSE).The continuing erosion of the efficacy of current antibiotics requires the discovery and development of new antibacterials that are not subject to existing mechanisms of target-based resistance. This can be accomplished by building derivatives of existing antibiotics which escape resistance mechanisms or by the development of entirely new chemical classes of antibiotics. The latter approach is preferred because preexisting target-based resistance mechanisms are unlikely to be present in the bacterial population. Here, we report MIC₉₀ values versus several problematic bacterial pathogens for a recently described series of bis-indole compounds (6, 7). MBX 1066 (Fig. ​(Fig.1),1), along with MBX 1090, 1113 and 1128 (7) were identified in a screen of the NCI repository for compounds active against Bacillus anthracis. The indole groups of MBX 1066 and MBX 1090 face each other in a symmetrical fashion (“head-to-head”), while they are positioned in a tandem arrangement (“head-to-tail”) in MBX 1113 and 1128. The head-to-head compounds were found to be more potent than the head-to-tail compounds against Gram-negative species while being nearly equipotent against Gram-positive species. MBX 1066 exhibited low cytotoxicity against HeLa cells (50% cytotoxic concentration [CC₅₀], 33 μg/ml) upon 3-day exposure, while the other compounds were slightly more cytotoxic (7). MBX 1066 displayed rapid bactericidal activity against both Gram-positive (Bacillus anthracis and B. subtilis) and Gram-negative (Yersinia pestis) bacteria (7) and demonstrated efficacy in murine models of Gram-positive (B. anthracis and S. aureus) and Gram-negative (Y. pestis) infections (7). MBX 1066 and related compounds bound serum proteins less than 25% (M. Butler, unpublished observation). Finally, experiments to isolate MBX 1066-resistant mutants by serial passage and spontaneous mutation selection were unsuccessful against both S. aureus and E. coli, although mutants resistant to a closely related compound, MBX 1090, were isolated (6, 7).Open in a separate windowFIG. 1.Structures of bis-indole compounds MBX 1066 and MBX 1162.We have conducted a structure activity relationship (SAR) program around the head-to-head compounds, typified by MBX 1066. While the molecular target(s) of these compounds is not known, the fact that they share some structural features with compounds that bind in the minor groove of duplex DNA (1) suggests that these compounds may inhibit DNA synthesis by binding to DNA. In fact, we have shown that they are potent inhibitors of DNA synthesis (7). However, their efficacy in murine models of infection, together with favorable in vitro selectivity indices, indicates that these compounds discriminate to some degree between bacterial and mammalian targets (7).Analogs of MBX 1066, particularly MBX 1162 (Fig. ​(Fig.1),1), exhibit improved Gram-negative activity while maintaining the Gram-positive potencies displayed by the parent compound. MBX 1162 is remarkably potent against antibiotic-resistant bacterial strains such as MDR A. baumannii, ESBL-producing Klebsiella pneumoniae, VRE, and MRSA, making it a promising new antibacterial agent. While MBX 1162 appeared somewhat more cytotoxic than MBX 1066 against HeLa cells (CC₅₀, 4 μg/ml) upon 3-day exposure, it retained the favorable features of MBX 1066, including bactericidal activity against both Gram-positive and Gram-negative pathogens, low serum binding (M. Butler, unpublished), and absence of susceptibility to resistance development (T. Opperman, unpublished observation), and its enhanced antibacterial activity provided selectivity index values (CC₅₀/MIC) comparable to those of MBX 1066 for Gram-negative species. In addition, MBX 1162 exhibited potent inhibition of DNA synthesis (T. Opperman and M. Butler, unpublished), suggesting its mechanism of action is similar to that of MBX 1066. Although we have observed an exceptionally broad antimicrobial profile for MBX 1066 and 1162 against single isolates of a variety of species, it is important to determine efficacy against larger groups of single species isolates, obtained from several clinical sources, looking specifically at populations of antibiotic-resistant clinical pathogens. To this end, we analyzed potencies against multiple strains of eight Gram-positive and eight Gram-negative species.Two hundred thirty-three Gram-positive strains and 180 Gram-negative aerobic strains were tested by the broth microdilution method (4) against MBX 1066 and 1162 as well as four comparator antibiotics. The comparator antibiotics were selected to be the most appropriate for each family as well as for verifying particular resistances and were thus different for Gram-positive versus Gram-negative isolates. These included linezolid (ChemPacifica), daptomycin (Cubist), vancomycin (Sigma-Aldrich), and imipenem (United States Pharmacopeia) for the Gram-positive aerobic bacteria and imipenem, tigecycline (Wyeth), gentamicin (Sigma-Aldrich), and ciprofloxacin (United States Pharmacopeia) for the Gram-negative aerobic bacteria. In addition, 18 isolates of the Gram-positive anaerobe Clostridium difficile were analyzed (3) using clindamycin (Sigma-Aldrich), imipenem, and metronidazole (Sigma-Aldrich) as comparators. The growth medium used in these studies was the CLSI-recommended Mueller-Hinton broth II (MHB II), with the exception of the streptococci (MHB II plus 2% lysed horse blood), Haemophilus influenza (HTM medium), and C. difficile (supplemented brucella broth). The quality control reference strains, S. aureus ATCC 29213, E. faecalis ATCC 29212, Streptococcus pneumoniae ATCC 49619, E. coli ATCC 25922, P. aeruginosa ATCC 27853, and Bacteroides fragilis ATCC 25285, were tested in accordance with CLSI methodology, and the results were within published ranges (5). The locations of the sources of the clinical isolates are listed in Table ​Table11.

TABLE 1.

Activities of MBX 1066 and MBX 1162 and selected comparators against Gram-positive and Gram-negative isolates

In Vitro Activity of Cephalosporin RWJ-54428 (MC-02479) against Multidrug-Resistant Gram-Positive Cocci

RWJ-54428 (MC-02479) is a novel cephalosporin that binds to penicillin-binding protein (PBP) PBP 2' (PBP 2a) of methicillin-resistant staphylococci. Its in vitro activity was assessed against 472 gram-positive cocci, largely selected as epidemiologically unrelated isolates with multidrug resistance. The MIC at which 50% of isolates are inhibited (MIC(50)) and MIC(90) of RWJ-54428 for methicillin-resistant Staphylococcus aureus (MRSA) were 1 and 2 microg/ml, respectively, whereas they were 0.5 and 0.5 microg/ml, respectively, for methicillin-susceptible S. aureus. The MIC(50) and MIC(90) were 1 and 4 microg/ml, respectively, for methicillin-resistant coagulase-negative staphylococci (MRCoNS), whereas they were 0.25 and 1 microg/ml, respectively, for methicillin-susceptible isolates. The highest MICs for MRSA and MRCoNS isolates were 2 and 4 microg/ml, respectively. The MIC(50) and MIC(90) of RWJ-54428 for Enterococcus faecalis were 0.5 and 1 microg/ml, respectively, but they were 4 and 8 microg/ml, respectively, for Enterococcus faecium. For penicillin-susceptible, -intermediate, and -resistant pneumococci, the MIC(90)s of RWJ-54428 were 0.03, 0.25, and 0.5 microg/ml, respectively, with the highest MIC for a pneumococcus being 1 microg/ml, recorded for a strain for which penicillin and cefotaxime MICs were 8 and 4 microg/ml. MICs for Lancefield group A, B, C, and G streptococci were < or =0.008 microg/ml; those for viridans group streptococci, including isolates not susceptible to penicillin, were from 0.015 to 0.5 microg/ml. RWJ-54428 did not select resistant mutants of MRSA or enterococci in challenge experiments and has the potential to be useful for the treatment of infections caused by gram-positive cocci.     

In Vitro Activity of Sodium Fusidate Against Anaerobic Bacteria

The microtiter broth dilution method was employed to determine the in vitro susceptibility of 525 recent clinical isolates of anaerobic bacteria to sodium fusidate. The minimal inhibitory concentrations of sodium fusidate ranged from 相似文献   

In Vitro Activity of the New Glycopeptide LY333328 against Multiply Resistant Gram-Positive Clinical Isolates

The in vitro activity of LY333328 was compared with those of vancomycin and teicoplanin against 425 gram-positive clinical isolates, including a variety of multiply resistant strains. LY333328 at ≤4 μg/ml inhibited all microorganisms tested, including methicillin- and teicoplanin-resistant staphylococci, glycopeptide-resistant enterococci, penicillin- and multiply resistant pneumococci, and viridans and beta-hemolytic streptococci.     

Comparison of Five Aminocyclitol Antibiotics In Vitro Against Enterobacteriaceae and Pseudomonas

The in vitro susceptibility of 163 strains of Enterobacteriaceae and 23 isolates of Pseudomonas aeruginosa to various concentrations of gentamicin, kanamycin, spectinomycin, tobramycin, and BB-K8, a new semisynthetic aminoglycoside antibiotic, was determined. Studies were performed in Mueller-Hinton agar and broth, and two different sizes of bacterial inocula were used. On a weight basis, gentamicin and tobramycin demonstrated comparable activity in vitro and were the most active of the five drugs tested against Escherichia coli, Klebsiella, Enterobacter, and Proteus species. All of these organisms were inhibited by gentamicin or tobramycin at concentrations of 5.0 mug or less/ml in agar with both inocula of bacterial cells. In addition, tobramycin was the most active drug against isolates of P. aeruginosa and gentamicin was the most active against Salmonella and Shigella species. Although kanamycin and BB-K8 demonstrated a high degree of activity against most Enterobacteriaceae, they were not the most active agents tested for any genus. Spectinomycin was the least active compound, and many isolates grew in concentrations higher than those readily attainable in serum.     

Effect of Clindamycin on the In Vitro Activity of Amikacin and Gentamicin Against Gram-Negative Bacilli

The in vitro effect of clindamycin on the inhibitory and bactericidal activity of amikacin (BB-K8) and gentamicin against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa was examined by the checkerboard technique in microtiter plates. Clindamycin (15 μg/ml) produced statistically significant increases in the minimal bactericidal concentrations of amikacin and gentamicin against E. coli and Klebsiellae at 2 and 4 h of incubation. The minimal bactericidal concentration against P. aeruginosa was not affected. Higher concentrations of clindamycin (20 to 25 μg/ml) reduced the minimal inhibitory and bactericidal concentrations of amikacin and gentamicin for E. coli at 18 h of incubation. The synergistic bactericidal activity of amikacin and carbenicillin against E. coli, but not P. aeruginosa, was also inhibited slightly by clindamycin (15 μg/ml). The clinical implications of this inhibition of the early bactericidal in vitro activity of aminoglycosides by clindamycin remain to be determined. Although these in vitro results have not been studied in clinical infections, it is conceivable that slight interference in early bacterial killing could alter the outcome of infection in the immunosuppressed patient.     

In Vitro Activity of Rosamicin and Erythromycin Against a Group of Nonfermenting Gram-Negative Bacilli

The in vitro inhibitory activity of rosamicin and erythromycin against 283 strains of nonfermenting, gram-negative bacilli was determined by using a broth dilution procedure. Rosamicin demonstrated greater activity than erythromycin against most strains tested. A number of species demonstrated significantly lower minimum inhibitory concentrations to rosamicin and would fall within the therapeutic range of the drug based on current pharmacological data.     

Comparative In Vitro Activity of Newer Cephalosporins Against Anaerobic Bacteria

The in vitro susceptibilities of 408 recent clinical isolates of anaerobic bacteria against cefaclor, cephalexin, cephalothin, cefazolin, cefamandole, and cefoxitin were compared by an agar dilution technique. Against gram-positive bacteria, especially peptococci, peptostreptococci, and propionibacteria, cephalexin and cefaclor were significantly less active than cephalothin (P < 0.05). Cephalexin was also less active than cephalothin against clostridia and lactobacillus (P < 0.05). Against gram-negative bacteria, major differences were observed primarily with Bacteroides fragilis, against which cephalexin, cefazolin and cefoxitin were all significantly more active than cephalothin (P < 0.001). At concentrations of 16 μg per ml, however, all cephalosporins showed high in vitro activity, except against Lactobacillus species and B. fragilis. Cephalothin, cefazolin and cefamandole were considerably more active against the former, whereas cefoxitin was distinctly more active against the latter.