Nai-Xun Chin

In vitro activity of sparfloxacin.

Sparfloxacin, a new fluoroquinolone, inhibited the majority of members of the family Enterobacteriaceae at less than or equal to 1 microgram/ml. It was less active than ciprofloxacin but more active than ofloxacin. Against Pseudomonas aeruginosa, it was less active than ciprofloxacin but twofold more active than ofloxacin. It inhibited Staphylococcus aureus and most Streptococcus pneumoniae and Streptococcus pyogenes isolates at 0.25 micrograms/ml, whereas ciprofloxacin and ofloxacin inhibited these isolates at 2 micrograms/ml. Bacteroides fragilis was inhibited by less than or equal to 2 micrograms/ml. Sparfloxacin was less active at an acidic pH and in the presence of Mg2+. Resistance to sparfloxacin was produced by repeated exposure, although the frequency of single-step mutants was less than 10(-9).

In vitro activity and beta-lactamase stability of a new carbapenem, SM-7338.

SM-7338, a new carbapenem, inhibited most members of the family Enterobacteriaceae at MICs of 0.015 to 0.25 microgram/ml, including Klebsiella oxytoca, Citrobacter freundii, Enterobacter cloacae, and Proteus vulgaris isolates resistant to cefotaxime, ceftazidime, piperacillin, and gentamicin. It was two- to eightfold more active than imipenem, but it inhibited Pseudomonas aeruginosa at 1 to 8 micrograms/ml, which was comparable to the activity of imipenem. Haemophilus, Neisseria, and Branhamella species were inhibited by less than or equal to 0.25 microgram/ml, which was superior to the activity of imipenem. SM-7338 inhibited Staphylococcus aureus and coagulase-negative staphylococci at 0.25 microgram/ml, but for methicillin-resistant isolates MICs were 4 to 16 micrograms/ml. Group A, B, and C streptococci and Streptococcus pneumoniae were inhibited by less than or equal to 0.03 microgram/ml. Bacteroides species, including clindamycin-resistant isolates, were inhibited by 0.25 microgram/ml. There was no major inoculum size effect, and the MBCs were within a dilution of the MICs. SM-7338 was more active than imipenem at an acid pH under anaerobic conditions. Plasmid beta-lactamases of TEM-1, TEM-2, TEM-3, TEM-5, SHV-1, SHV-2, PSE-1, PSE-2, PSE-3, OXA-2, OXA-3, OXA-4, OXA-5, and OXA-7; Staphylococcus aureus enzymes; and the chromosomal beta-lactamases P-99 and K-1; Morganella species; and Proteus vulgaris did not hydrolyze SM-7338. The repeated transfer of organisms increased the MICs of SM-7338, as it did the MICs of imipenem.

Synergy of ciprofloxacin and azlocillin in vitro and in a neutropenic mouse model of infection

Combinations of ciprofloxacin with azlocillin, piperacillin and ticarcillin were tested in vitro against clinical isolates. Azlocillin plus ciprofloxacin showed synergy against 30% ofPseudomonas aeruginosaisolates; it was either synergistic or additive against 78% of all isolates tested even those resistant to the beta-lactam. Synergism was rarely noted forKlebsiella pneumoniae, Escherichia coli, Enterobacterspp. orBranhamellaspp. isolates. Minimum inhibitory concentrations of ciprofloxacin plus azlocillin, plus piperacillin and plus ticarcillin againstPseudomonasspp. were reduced 4 or 2 fold, respectively. However, the combination azlocillin plus ciprofloxacin showed primarily indifference against gram-positive strains. Neutropenic mice infected with a lethal challenge ofPseudomonasspp. were protected by a combination of azlocillin and ciprofloxacin. Its additive and/or synergistic effects and expanded spectrum of activity against streptococci, methicillin-resistant staphylococci and JK corynebacteria may provide an alternative to traditional therapy.

In vitro activity against aerobic and anaerobic gram-positive and gram-negative bacteria and beta-lactamase stability of RS-533, a novel carbapenem.

RS-533 is a novel carbapenem antibiotic. Its activity was compared with that of imipenem and the new cephalosporins, aztreonam, piperacillin, and tobramycin. RS-533 had activity comparable to that of imipenem, inhibiting the majority of the Enterobacteriaceae, streptococci, staphylococci, and Bacteroides species at concentrations of less than or equal to 2 micrograms/ml. RS-533 inhibited Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens resistant to ceftazidime, aztreonam, and cefoperazone, but RS-533 did not inhibit all methicillin-resistant Staphylococcus aureus or Pseudomonas maltophilia. It inhibited tobramycin-resistant members of the Enterobacteriaceae and Pseudomonas aeruginosa. RS-533 was stable against attack by common chromosomal and plasmid-mediated beta-lactamases and was an effective inhibitor of many beta-lactamases.

Antibacterial activity of coumermycin alone and in combination with other antibiotics.

Coumermycin has been shown to inhibit Staphylococcus aureus and Staphylococcus epidermidis strains that are susceptible and those that are resistant to methicillin at concentrations less than or equal to 0.05 micrograms/ml. Listeria monocytogenes and Corynebacterium spp. resistant to cephalosporins were inhibited by less than or equal to 1.6 micrograms of coumermycin ml, and streptococcal species, with the exception of Streptococcus faecalis, were inhibited by 0.1 micrograms/ml. Cross-resistance with beta-lactams or aminoglycosides was not found. Coumermycin acted synergistically with ofloxacin, norfloxacin, and enoxacin against S. aureus but did not show synergy when combined with nafcillin, vancomycin, or rifampin. Coumermycin did not inhibit members of the family Enterobacteriaceae or Pseudomonas aeruginosa.

In vitro activity and beta-lactamase stability of two oral cephalosporins, ceftetrame (Ro 19-5247) and cefetamet (Ro 15-8074).

Ceftetrame (Ro 19-5247) and cefetamet (Ro 15-8074), two new orally administered aminothiazolyl imimomethoxy cephalosporins, inhibited hemolytic streptococci and Streptococcus pneumoniae at less than or equal to 0.5 micrograms/ml but were less active against staphylococci than were cephalexin and cefaclor. They did not inhibit S. faecalis, S. faecium, Listeria monocytogenes, Corynebacterium JK species, or Pseudomonas aeruginosa. Haemophilus influenzae, Branhamella catarrhalis, and Neisseria gonorrhoeae, including ampicillin-resistant isolates, were inhibited at less than 0.25 micrograms/ml. Both agents inhibited Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Proteus mirabilis, Salmonella species, Shigella species, Citrobacter diversus, and Aeromonas hydrophila resistant to ampicillin, cephalexin, and cefaclor at less than or equal to 2 micrograms/ml, although many isolates of Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens resistant to cefotaxime were not inhibited by these agents. A marked inoculum effect was noted for Enterobacteriaceae carrying the Richmond-Sykes type 1A chromosomally mediated beta-lactamases, but plasmid-mediated beta-lactamases did not hydrolyze the compounds. Both drugs inhibited the chromosomally mediated beta-lactamase of E. cloacae, P99.

Resistance to ciprofloxacin appearing during therapy

The development of resistance to ciprofloxacin in nine clinical isolates of Pseudomonas aeruginosa was investigated. Isolates had increases in minimal inhibitory concentrations (MICs) from 0.25 to 16 micrograms/ml. The isolates also became resistant to ofloxacin and norfloxacin, but did not show increases in MICs to aminoglycosides, antipseudomonas penicillins, or cephalosporins. One isolate from a patient with endocarditis showed a reduction in a 43-kD outer membrane protein and simultaneous increase in the imipenem MIC. This isolate also showed impaired uptake of ciprofloxacin. Respiratory isolates from cystic fibrosis patients did not show loss of outer membrane protein. MICs were lowered by ethylene diaminetetra-acetic acid, suggesting changes in lipopolysaccharide. Resistant isolates were synergistically inhibited by combinations of ciprofloxacin plus tobramycin or ceftazidime, but MICs remained beyond the achievable serum level.

In vitro Activity of Cefquinome, a New Cephalosporin, Compared with Other Cephalosporin Antibiotics

The in vitro activity of cefquinome, a new aminothiazolyl cephalosporin with a C-3 bicyclic pyridinium group, was compared with ceftazidime, cefpirome, and cefepime. Cefquinome inhibited members of the Enterobacteriaceae at less than or equal to 0.5 microgram/ml for Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Citrobacter diversus, Salmonella Shigella, Proteus mirabilis, Morganella, and Providencia. Although most Citrobacter freundii and Enterobacter cloacae were inhibited by less than 2 micrograms/ml, some strains resistant to ceftazidime were resistant, [minimum inhibitory concentration (MIC) greater than 16 micrograms/ml]. Serratia marcescens were inhibited by less than 1 microgram/ml and Pseudomonas aeruginosa by 8 micrograms/ml similar to the activity of cefepime. The majority of Haemophilus influenzae and Neisseria gonorrhoeae were inhibited by less than 0.25 microgram/ml. Most enterococci had cefquinome MICs of 4-8 micrograms/ml. Cefquinome was extremely active against group-A streptococci and Streptococcus pneumoniae with MICs less than 0.12 microgram/ml. 90% of methicillin-susceptible Staphylococcus aureus 90% were inhibited by 2 micrograms/ml. Overall, the in vitro activity of cefquinome was comparable with aminothiazolyl cephalosporins. It inhibited some Enterobacter and Citrobacter freundii resistant to ceftazidime as did cefpirome and cefepime. Cefquinome was not destroyed by the common plasmid beta-lactamases TEM-1, TEM-2, SHV-1, or by the chromosomal beta-lactamases of Klebsiella, Branhamella, and Pseudomonas, but it was hydrolyzed by TEM-3, TEM-5, and TEM-9. Its activity was not adversely decreased in different medium or protein, and minimum bactericidal concentrations (MBCs) for most species except for Enterobacter were within a dilution of MICs.

Resistance of Xanthomonas maltophilia to antibiotics and the effect of beta-lactamase inhibitors

We examined the susceptibility of 50 isolates of Xanthomonas maltophilia and the effect of beta-lactamase inhibitors upon the susceptibility. The majority of isolates were resistant to azlocillin, piperacillin, mezlocillin, ticarcillin, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, and ceftazidime. All isolates were resistant to imipenem, CGP 31608, aztreonam, and carumonam. Although disk susceptibility tests showed that the combination of clavulanate with ticarcillin inhibited many isolates, at a ratio of 1:20 few isolates were susceptible to the combination. Addition of clavulanate to aztreonam and to imipenem failed to make organisms susceptible. Sulbactam combined with cefoperazone made some organisms susceptible, but ampicillin-sulbactam was ineffective, whereas tazobactam combined with piperacillin at a ratio of 1:4 made half the isolates have MICs of 32 micrograms/ml or less. The beta-lactamases from the isolates hydrolyzed all of the beta-lactams.

The in vitro activity and beta-lactamase stability of cefpirome (HR 810), a pyridine cephalosporin agent active against staphylococci, enterobacteriaceae and pseudomonas aeruginosa

SummaryThein vitro activity of cefpirome, a new cyclopyridinium cephalosporin, was evaluated against 947 aerobic and anaerobic bacteria. Cefpirome inhibited 90% ofEscherichia coli, Klebsiella spp.,Citrobacter diversus, Morganella morganii, Proteus vulgaris, Proteus mirabilis, Aeromonas spp.,Salmonella spp.,Shigella spp. andHaemophilus andNeisseria species at ≤0.4 mg/l. It had activity comparable to that of cefotaxime, ceftizoxime, ceftazidime, aztreonam, and moxalactam against these species. Only a fewCitrobacter freundii, Enterobacter spp. andSerratia marcescens had MICs above 3.1 mg/l. The activity of cefpirome againstPseudomonas aeruginosa, 90% MIC of 12.5 mg/l, was superior to piperacillin, moxalactam, cefotaxime and cefoperazone. The 90% MIC againstStaphylococcus aureus was 0.8 mg/l, but methicillin-resistant staphylococci were not inhibited. Cefpirome was not significantly hydrolyzed by most plasmid beta-lactamases (TEM, SHV-1, PSE, OXA) nor by chromosomal enzymes (P99,Branhamella catarrhalis, Kl). Cefpirome did not inhibit chromosomal or plasmid betalactamases. Mice systemically infected withE. coli, Klebsiella pneumoniae, P. aeruginosa andS. aureus were protected by concentrations of cefpirome ranging from 0.85 mg/kg forK. pneumoniae to 4.467 mg/kg forP. aeruginosa.ZusammenfassungCefpirom, ein neues Cyclopyridin-Cephalosporin, wurdein vitro auf seine Aktivität gegen 947 aerobe und anaerobe Bakterien geprüft. In Konzentrationen von ≤0,4 mg/l hemmte Cefpirom 90% der Stämme vonEscherichia coli, Klebsiella sp.,Citrobacter diversus, Morganella morganii, Proteus vulgaris, Proteus mirabilis, Aeromonas spp.,Salmonella spp.,Shigella spp. undHaemophilus undNeisseria species. Seine Aktivität gegen diese Species war mit der von Cefotaxim, Ceftizoxim, Ceftazidim, Aztreonam und Moxalactam vergleichbar. Die MHK-Werte lagen nur für einigeCitrobacter freundii, Enterobacter spp. undSerratia marcescens über 3,1 mg/l. Die Aktivität von Cefpirom gegenPseudomonas aeruginosa war der von Piperacillin, Moxalactam, Cefotaxim und Cefoperazon überlegen; für 90% der Stämme lagen die MHK-Werte bei 12,5 mg/l. 90% der MHK-Werte fürStaphylococcus aureus betrugen 0,8 mg/l, methicillinresistente Staphylokokken wurden jedoch nicht gehemmt. Eine hydrolytische Spaltung von Cefpirom kam weder durch die Mehrzahl der plasmidgebundenen Betalactamasen (TEM, SHV-1, PSE, OXA) noch durch chromosomal gebundene Enzyme (P 99,Branhamella catharrhalis, K1) in signifikantem Ausmaß zustande. Chromosomale oder plasmidgebundene Betalactamasen wurden von Cefpirom nicht gehemmt. Bei systemischer Infektion mitE. coli, Klebsiella pneumoniae, P. aeruginosa undS. aureus hatte Cefpirom protektive Wirkung in Dosen, die von 0,85 mg/kg beiK. pneumoniae bis 4,467 mg/kg beiP. aeruginosa reichten.