Pulmonary disposition of roxithromycin (RU 28965), a new macrolide antibiotic.

The penetration of roxithromycin (RU 28965), an ether oxime derivative of erythromycin, into the cells and fluid lining the epithelial surface of the lower respiratory tract was studied by performing fiber-optic bronchoscopy with bronchoalveolar lavage on eight patients who had received roxithromycin at 300 mg perorally every 12 h for 5 days. The apparent volume of epithelial lining fluid recovered by bronchoalveolar lavage was determined by using urea as an endogenous marker. There was a significant relationship (r = 0.75; P less than 0.02) between roxithromycin levels in plasma and epithelial lining fluid, with a correlation whose slope suggested that the level of drug penetration into the lining fluid was 0.2. Concentrations of the antibiotic in cells recovered by bronchoalveolar lavage (21 +/- 10 micrograms/ml) were 2 and 10 times higher than in plasma (11.4 +/- 5.7 micrograms/ml) and epithelial lining fluid (2.0 +/- 1.7 micrograms/ml), respectively. Thus, when administered perorally in humans, roxithromycin is markedly accumulated by resident alveolar macrophages in concentrations largely exceeding the MBCs of the drug for most facultative intracellular pathogens including Legionella pneumophila, despite low concentrations in the epithelial lining fluid.     

Comparative in vitro activities of ofloxacin, difloxacin, ciprofloxacin, and other selected antimicrobial agents against Brucella melitensis.

The in vitro activities of three quinolones (ofloxacin, difloxacin, and ciprofloxacin) were compared with those of trimethoprim-sulfamethoxazole, streptomycin, tetracycline, and rifampin against 47 Brucella melitensis strains. Ofloxacin was the most active of the test antimicrobial agents. It inhibited 90% of B. melitensis strains at a concentration of 0.02 micrograms/ml.     

In vitro activity of HR 810, a new cephalosporin.

The in vitro susceptibility of 409 clinical isolates to HR 810, a new cephalosporin, was evaluated and compared with their susceptibility to aztreonam, cefazolin, ceftazidime, imipenem, moxalactam, piperacillin, and gentamicin. On a weight basis, the activity of HR 810 against gram-negative bacilli was equivalent or superior to that of the other beta-lactam agents except imipenem.     

In vitro evaluation of three new macrolide antimicrobial agents, RU28965, RU29065, and RU29702, and comparisons with other orally administered drugs.

Three new macrolide drugs (RU28965, RU29065, and RU29702) were compared in vitro with erythromycin and five other orally administered antimicrobial agents by using 733 recent clinical isolates. All of the investigational macrolides had a spectrum very similar to that of erythromycin, but with slightly higher (two- to fourfold) minimum inhibitory concentrations against Haemophilus influenzae, staphylococci, and streptococci including Streptococcus faecalis. RU29065 and RU29702 were more active than erythromycin against Neisseria gonorrhoeae and Neisseria meningitidis. The drugs appeared to be predominantly bacteriostatic and were ineffective against gram-negative bacilli, and their minimum inhibitory concentrations were greatly increased by high inoculum concentrations. Cross-resistance between the macrolides was nearly complete, favoring the use of a single agent for in vitro susceptibility test if in vivo therapeutic differences are not observed.     

Activity of roxithromycin (RU 28965), a macrolide, against Toxoplasma gondii infection in mice.

Roxithromycin (RU 28965), an ether oxime derivative of erythromycin, protected mice against a lethal infection with the virulent RH strain of Toxoplasma gondii. Therapy begun 24 h before, 2 h after, and 24 h after infection with 2 X 10(3) tachyzoites protected 90, 80, and 50% of the mice, compared with 0% of untreated controls (P less than 0.05 to 0.001). Toxoplasma was isolated in less than 20% of surviving roxithromycin-treated mice.     

In vitro activities of U-63366, a spectinomycin analog; roxithromycin (RU 28965), a new macrolide antibiotic; and five quinolone derivatives against Haemophilus ducreyi.

The in vitro activities of the new spectinomycin analog U-63366, the new macrolide roxithromycin (RU 28965), and five new quinolone derivatives (pefloxacin, rosoxacin, norfloxacin, ofloxacin, and ciprofloxacin) were studied against 23 multiresistant strains of Haemophilus ducreyi (beta-lactamase producers) isolated in Paris and were compared with the activities of tetracycline, minocycline, chloramphenicol, streptomycin, kanamycin, gentamicin, spectinomycin, erythromycin, and nalidixic acid. All strains were uniformly susceptible to the seven new antibiotics tested. Ciprofloxacin had the greatest inhibitory effect in vitro (the MIC for 90% of the strains tested [MIC90] was 0.016 microgram/ml), and U-63366 was the most active aminoglycoside-aminocyclitol antibiotic (MIC90, 0.25 microgram/ml).     

Comparative in vitro activities of ten antimicrobial agents against bacterial enteropathogens.

The in vitro susceptibilities of 50 strains of Salmonella spp., 80 strains of Shigella spp., and 50 enterotoxigenic Escherichia coli, 14 Yersinia enterocolitica, 6 Aeromonas hydrophila, 4 Plesiomonas shigelloides, 9 Vibrio parahaemolyticus, and 30 Campylobacter jejuni strains that were recently isolated from worldwide sources were determined for 10 antimicrobial agents. The antimicrobial agents tested included ampicillin, bicozamycin, doxycycline, enoxacin (CI-919), erythromycin, furazolidone, amdinocillin, norfloxacin, trimethoprim, and trimethoprim-sulfamethoxazole. Ampicillin resistance occurred frequently in strains of Salmonella and Shigella spp. and enterotoxigenic E. coli strains. The most active agents against all of the bacteria tested were enoxacin and norfloxacin. Furazolidone and amdinocillin were also highly active against the majority of strains. Trimethoprim and trimethoprim-sulfamethoxazole were inhibitory at low concentrations against all test except C. jejuni isolates. The in vitro results of this study confirm the high prevalence of bacterial resistance to ampicillin. However, this work also identifies four antimicrobial agents, enoxacin, furazolidone, norfloxacin, and amdinocillin, that would be appropriate for further testing in clinical trials.     

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.     

In vitro activity of the new macrolide antibiotic roxithromycin (RU 28965) against clinical isolates of Haemophilus influenzae.

The in vitro activity of the new macrolide antibiotic roxithromycin (RU 28965) was compared with the activities of five other orally absorbable antimicrobial agents against 100 clinical isolates of Haemophilus influenzae. Roxithromycin MICs were generally twofold to fourfold higher than those of erythromycin; the MIC for 90% of the strains for roxithromycin was 8 micrograms/ml.     

Beta-lactamase stability of cefpirome (HR 810), a new cephalosporin with a broad antimicrobial spectrum.

Cefpirome was highly stable to hydrolysis by various beta-lactamases, although it was hydrolyzed to some extent by R plasmid-mediated penicillinase of Richmond-Sykes type Va/b and by chromosomal cephalosporinases from Bacteroides species. The compound had a very low affinity for cephalosporinases from Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, and Proteus vulgaris. Cefpirome showed strong antimicrobial activity against eight beta-lactamase (cephalosporinase)-producing strains which have become resistant to broad-spectrum cephalosporins; especially against E. cloacae and C. freundii, it had the highest activity among the cephalosporins used. Its activity against ampicillin-resistant R plasmid-containing transconjugant isolates of Escherichia coli was as high as that against the recipient strain E. coli chi 1037. The inducer activity of cefpirome in S. marcescens and P. vulgaris increased dose dependently, whereas cephamycin derivatives showed high inducer activity at low concentrations. A relatively low affinity of cefpirome for beta-lactamases is considered to be one of the reasons for its high antimicrobial activity against such enzyme-producing strains. In addition, other factors such as good penetration through the outer membrane and affinity for the target sites may also be involved in the high activity of cefpirome.     

In vitro comparison of the activity of RU 28965, a new macrolide, with that of erythromycin against aerobic and anaerobic bacteria.

RU 28965, a novel macrolide antibiotic, inhibited most gram-positive species at concentrations similar to that of erythromycin but was not active, even at alkaline pH, against Pseudomonas spp. or members of the family Enterobacteriaceae. Staphylococci and streptococci resistant to erythromycin were resistant to RU 28965. RU 28965 inhibited Haemophilus influenzae, including a number of beta-lactamase, ampicillin-resistant isolates, and Neisseria meningitidis and Neisseria gonorrhoeae at concentrations similar to those of erythromycin. Against anaerobic species, Bacteroides fragilis and Clostridia and Fusobacterium spp., RU 28965 was less active than erythromycin, but its activity against Campylobacter and Legionella spp. was similar to that of erythromycin.     

In vitro activities of ciprofloxacin, ofloxacin, norfloxacin and rosoxacin compared with cinoxacin and trimethoprim

The in vitro activities of ciprofloxacin, ofloxacin, norfloxacin, rosoxacin, cinoxacin and trimethoprim have been compared. An agar dilution method has been employed for the measurement of minimal inhibitory concentrations (MICs). 426 clinical, bacterial urinary isolates mainly from hospitalised patients were included; all common urinary tract pathogens were represented. The newer quinolones were highly active against Enterobacteriaceae species, Pseudomonas aeruginosa and Acinetobacter calcoaceticus. Ciprofloxacin was the most active agent against these organisms (MICs less than or equal to 2 mg/l). A few strains of Escherichia coli and Klebsiella were resistant to rosoxacin (MIC greater than or equal to 128 mg/l). Cinoxacin and trimethoprim were considerably less active against gram-negative strains. The new quinolones were also active against staphylococci of various species and enterococci (MICs less than or equal to 4 mg/l) except for rosoxacin for which 16 mg/l was needed to inhibit all gram-positive isolates. Cinoxacin was virtually inactive against this group whereas trimethoprim showed variable activity.     

Comparative in vitro activities of ciprofloxacin, gemifloxacin, grepafloxacin, moxifloxacin, ofloxacin, sparfloxacin, trovafloxacin, and other antimicrobial agents against bloodstream isolates of gram-positive cocci

The in vitro activity of gemifloxacin against 316 bloodstream isolates of staphylococci, pneumococci, and enterococci was compared with the activities of six fluoroquinolones and three other antimicrobial agents. Of the antimicrobial agents tested, gemifloxacin was the most potent against penicillin-intermediate and -resistant pneumococci, methicillin-susceptible and -resistant Staphylococcus epidermidis isolates, and coagulase-negative staphylococci.     

Comparative antimycobacterial activities of ofloxacin, ciprofloxacin and grepafloxacin.

Infections caused by non-tuberculous mycobacteria and multidrug-resistant Mycobacterium tuberculosis are difficult to treat. New compounds potentially active against these bacteria are therefore constantly being sought. Among them is grepafloxacin, a new C5 fluoroquinolone. A panel of 130 isolates of mycobacteria including 33 M. tuberculosis isolates and 97 isolates of different species of atypical mycobacteria were analysed for susceptibility to grepafloxacin, ofloxacin and ciprofloxacin. The MICs of these fluoroquinolones were determined using the agar-dilution method. Different mycobacterial species showed different degrees of susceptibility to grepafloxacin, ofloxacin and ciprofloxacin but little difference was observed between the MICs of the three antibiotics against strains of the same mycobacterial species. In addition, to evaluate the intracellular activity of these drugs, six strains of mycobacteria were studied using a human-macrophage infection model. Preliminary results of macrophage experiments showed that grepafloxacin was more active than ofloxacin and ciprofloxacin, particularly against Mycobacterium kansasii and, to a lesser degree, against Mycobacterium avium complex and Mycobacterium marinum. However, the three fluoroquinolones had comparable activities against M. tuberculosis.     

Comparative activities of ciprofloxacin (Bay o 9867), norfloxacin, pipemidic acid, and nalidixic acid.

An agar dilution method was used to measure the minimal inhibitory concentrations of ciprofloxacin (Bay o 9867), norfloxacin, pipemidic acid, and nalidixic acid against 496 clinical isolates. Ciprofloxacin and norfloxacin were active against all species tested (90% minimal inhibitory concentrations less than or equal to 8 micrograms/ml), although ciprofloxacin was somewhat more active, e.g., against gram-positive cocci. Pipemidic acid and nalidixic acid were active against most of the members of the Enterobacteriaceae, but Klebsiella species and Providencia stuartii were only inhibited by a high concentration of nalidixic acid.     

Comparative antimicrobial activity of enoxacin, ciprofloxacin, amifloxacin, norfloxacin and ofloxacin against 177 bacterial isolates

The in-vitro antimicrobial activity of five new quinolones, enoxacin (CI-919, AT-2266), ciprofloxacin (Bay o 9867), amifloxacin (WIN 49375) norfloxacin (MK 0366), and ofloxacin (ORF 18489), was compared against 104 strains of Enterobacteriaceae, 51 Pseudomonas species, 7 Acinetobacter calcoaceticus var. anitratus, and 15 enterococci. In general the quinolones tested were active against most bacterial strains. Ciprofloxacin was the most active with MIC90 for all genera tested ranging from 0.03 to 4.0 mg/l. The range of MIC90 for enoxacin and amifloxacin was 0.06 to 16.0 mg/l, for ofloxacin 0.25 to 8.0 mg/l, and for norfloxacin 0.06 to 32.0 mg/l. All strains of P. aeruginosa tested were resistant to amikacin (MIC greater than or equal to 16 mg/l); those resistant by virtue of inactivating enzyme production were less susceptible to ciprofloxacin, ofloxacin, and norfloxacin than those strains exhibiting decreased uptake of amikacin. Susceptibility to enoxacin and amifloxacin was not affected by the mechanism of aminoglycoside resistance. Of 65 strains tested with four quinolones using log and lag phase bacterial growth, the MICs in log phase growth were one to two dilutions higher for 42% of strains tested with amifloxacin, 33% of those tested with norfloxacin, and 23% for those tested with enoxacin and ciprofloxacin.     

Comparative in vitro exoenzyme-suppressing activities of azithromycin and other macrolide antibiotics against Pseudomonas aeruginosa.

The inhibitory effects of azithromycin (AZM), a new 15-membered macrolide antibiotic, on the production of exotoxin A, total protease, elastase, and phospholipase C by Pseudomonas aeruginosa were determined, and the virulence-suppressing effects of AZM were compared with those of erythromycin (EM), roxithromycin (RXM), and rokitamycin (RKM). The effect of exposure of P. aeruginosa PA103 or B16 in cultures to sub-MICs of these macrolide antibiotics on the production of exoenzymes was determined. AZM suppressed the in vitro production of extracellular and intracellular exotoxin A by P. aeruginosa PA103 more than did EM, even at a concentration of only 2 micrograms/ml. At concentrations of between 4 and 32 micrograms/ml, AZM also inhibited total protease, elastase, and phospholipase C production by P. aeruginosa B16 more than did EM, RXM, and RKM. AZM was effective in suppressing exotoxin A and total protease production through 24 h of incubation in the presence of drug at sub-MICs, but it had no significant effect on either the growth of P. aeruginosa or its total protein production. Moreover, at a concentration of 4 micrograms/ml, AZM suppressed exoenzyme production by other strains of P. aeruginosa more than did EM. These findings indicate that AZM, EM, RXM, and RKM each has an inhibitory effect on exoenzyme production separate from the antimicrobial effect and that, of these macrolides, AZM has the strongest virulence-suppressing effect.     

In vitro activity of RU29246. The metabolite of a new HR916 cephalosporin ester.

Compound RU29246 (RU) is the active metabolite of an orally absorpted cephalosporin ester HR916. The RU spectrum of activity includes the majority of Enterobacteriaceae species, Haemophilus influenzae, pathogenic Neisseria spp., Moraxella catarrhalis, Acinetobacter antiratus, staphylococci, and Streptococcus spp. Pseudomonas species and enterococci were routinely resistant to RU. The RU spectrum was most similar to cefixime against the Gram-negative bacilli and to cefuroxime against the Gram-positive organisms. RU was bactericidal and its mean inhibitory concentrations (MICs) were not greatly increased by high inoculum concentrations. Many strains producing various beta-lactamases generally remained susceptible to RU by MIC tests. However, isolates with extended broad spectrum beta-lactamases capable of hydrolyzing cefotaxime and ceftazidime were also resistant to RU. Broth and agar RU MICs were comparable. Its activity was increased against enterococci in the presence of blood products.     

Comparative in vitro activity of cefodizime, ceftazidime, aztreonam, and other selected antimicrobial agents against Neisseria gonorrhoeae.

The in vitro activities of three new beta-lactam antimicrobial agents, cefodizime, ceftazidime, and aztreonam (formerly azthreonam), were compared with those of cefotaxime, cefuroxime, cefoxitin, and penicillin against 100 beta-lactamase-negative and 42 beta-lactamase-positive Neisseria gonorrhoeae strains. The three new antimicrobial agents showed excellent activity against N. gonorrhoeae regardless of beta-lactamase production. Cefodizime was as active as cefotaxime and more active than the other test antimicrobial agents. It inhibited all isolates at a concentration of less than or equal to 0.016 micrograms/ml.     

In-vitro evaluation of cefpirome (HR 810), teicoplanin and four other antimicrobials against enterococci

In-vitro activities of cefpirome (HR 810), a fourth generation cephalosporin, and teicoplanin were compared with those of ampicillin, piperacillin, and vancomycin against 56 clinical isolates of enterococci. Cefpirome had good activity with the MIC90 and MBC90 being 4 and 16 mg/l. Ampicillin and piperacillin had MBC90 of 4 and 16 mg/l. Teicoplanin was extremely active with the MIC90 being 1.6 mg/l while vancomycin had poor cidal activity with the MBC90 being 16 mg/l. A decrease in activity of cefpirome was noted when the inoculum size was increased from 10(3) to 10(7) organisms per ml. Synergy was demonstrated against most Streptococcus faecium isolates with a combination of cefpirome and gentamicin or piperacillin. Against Str. faecalis, with a similar combination, synergy was seen in less than 50% isolates. No antagonism was noted with any of the antibiotic combinations.