Comparative antimicrobial activity of the new macrolide flurithromycin against respiratory pathogens

The activity of flurithromycin againstHaemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Branhamella catarrhalis andStaphylococcus aureus was determined by the agar dilution method. Flurithromycin showed high activity againstStreptococcus pneumoniae, Streptococcus pyogenes andBranhamella catarrhalis (MIC90=0.032–0.25 mg/l). Its MIC90 value againstHaemophilus influenzae strains was 4.0 mg/l and 16 mg/l againstStaphylococcus aureus strains. Flurithromycin has promising antibacterial activity which warrants clinical trials.     

Comparative in vitro activity of the new oral macrolide azithromycin

The in vitro activity of the new oral macrolide azithromycin was compared with that of erythromycin against gram-positive and gram-negative aerobic and anaerobic bacteria. Ninety percent of hemolytic streptococci groups A and B, andStreptococcus pneumoniae were inhibited by 0.5 µg/ml. Activity of azithromycin was similar to that of erythromycin; erythromycin-resistant staphylococci and streptococci were not inhibited. Azithromycin was more active than erythromycin againstHaemophilus influenzae (MIC90 1 µg/ml) andNeisseria gonorrhoeae. It inhibitedCampylobacter spp. andPasteurella multocida, and had an MIC50 of 8 µg/ml forEscherichia coli, Salmonella spp.,Shigella spp. andYersinia enterocolitica compared to an erythromycin value of > 64 µg/ml.     

Effects of environmental factors on the in vitro potency of azithromycin

The effects of media, pH, cations, serum, CO₂ or anaerobic atmosphere, inoculum size and time of incubation on the in vitro potency of azithromycin were determined. The potency of azithromycin against all genera was particularly sensitive to changes in pH. The MIC forStaphylococcus aureus strains ranged from 50 µg/ml at pH 6 to 0.025 µg/ml at pH 8; for erythromycin the MIC change was less (1.6 to 0.05 µg/ml). Incubation for 18 h in 5 % CO₂ or an anaerobic atmosphere (10 % CO₂, 10 % H₂, 80 % N₂) lowered the pH by approximately 0.8 units with gram-negative organisms and 0.4 units with gram-positive organisms. This resulted in an MIC eight times greater than the aerobic MIC. In addition, the MIC100 for azithromycin and erythromycin againstBacteroides strains growing in Wilkins-Chalgren broth fell from 3.1 µg/ml in the anaerobic atmosphere to 0.2 and 0.4 µg/ml, respectively, when using the Oxyrase enzyme system to remove oxygen. With the Oxyrase system, the pH of the medium at the MIC remained at 7.2, while it fell to 6.7 in the anaerobic gas mixture. An increase in potency for both agents was also observed with other anaerobic species when using the Oxyrase system. The addition of serum produced an increase in potency of azithromycin and erythromycin that correlated with an increase in pH during incubation, despite the use of buffered media. Adding cations to Mueller-Hinton broth resulted in increased MICs for gram-negative organisms; the highest increases observed were four-fold forEscherichia coli. The activity of control antibiotics was not affected to the same degree as that of azithromycin. Increasing the incubation period from 24 to 48 h did not change the MIC values of azithromycin forStaphylococcus aureus orEscherichia coli; however, the MBC values were lower at 48 h and equalled the MIC values. Inoculum size or manner of preparation had no significant effect on the potency of azithromycin.     

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.     

Spectrum of activity of azithromycin

In recent years, a number of newer macrolides have been developed. One such antibiotic is azithromycin, which has a 15-membered ring structure and is classed as an azalide. The limitations of erythromycin and the discovery of pathogenic bacteria such asCampylobacter, Legionella andChlamydia species provide incentives to study the usefulness of newer antibiotics of this class. Azithromycin has good activity against staphylococci, streptococci,Moraxella catarrhalis and other rapidly growing pyogenic bacteria. The good activity of azithromycin againstHaemophilus influenzae (MIC90 0.5 mg/l) is particularly important as erythromycin has only marginal activity against this organism. Azithromycin has also been shown to be more potent than the macrolides againstEnterobacteriaceae. In common with erythromycin and tetracycline, the agent has good activity againstLegionella, Chlamydia andCampylobacter. Opportunistic infections involvingToxoplasma gondii andPneumocystis carinii are an increasing problem and azithromycin is particularly interesting in view of its activity against these difficult-to-treat organisms.     

In vitro activity of cefcanel versus other oral cephalosporins

Cefcanel is a new orally absorbed cephalosporin. Its activity was compared with that of cefuroxime, cefaclor, cephalexin, and cefixime against grampositive and negative aerobic and anaerobic bacteria. Cefcanel had excellent activity against methicillin-susceptibleStaphylococcus aureus andStaphylococcus epidermidis, MIC90 1 µg/ml, superior to the other oral cephalosporins. However, methicillin-resistant staphylococci were resistant, MIC 16 µg/ml.Streptococcus pyogenes andStreptococcus pneumoniae were inhibited by 0.015–1 µg/ml, concentrations comparable to other cephalosporins.Clostridium spp. were inhibited by 0.25 µg/ml, 8- to 128-fold lower concentrations than were found for other agents, but the MICs were >64 µg/ml forBacteroides spp. The MIC90 forMoraxella catarrhalis was 1 µg/ml, similar to cefuroxime but 16-fold greater than the MICs of cefixime.Escherichia coli andKlebsiella pneumoniae which were high beta-lactamase producers were resistant, MICs >64 µg/ml, and 50 % ofEnterobacter cloacae andCitrobacter freundii were resistant. Cefcanel was hydrolyzed by TEM-1, TEM-3 and Moraxella Bro-1 beta-lactamases.Escherichia coli containing TEM-1, 2, 3, 5, 7, and 9 had cefcanel MICs of 16 µg/ml. Although cefcanel inhibited gram-positive species as well as or at lower concentrations than other cephalosporins, it lacked activity against gram-negative species that produced common plasmid beta-lactamase although it inhibitedHaemophilus influenzae carrying TEM-1.     

In vitro activity of azithromycin and erythromycin against organisms associated with bacterial vaginosis and chancroid

The in vitro activity of the new macrolide azithromycin and erythromycin againstHaemophilus ducreyi, Gardnerella vaginalis, Bacteroides spp. andMobiluncus spp. was compared.Gardnerella vaginalis, Mobiluncus spp. andHaemophilus ducreyi were highly susceptible to both agents but azithromycin was more effective overall against all three groups of organisms. The activity of both antibiotics againstBacteroides spp. varied greatly, but azithromycin was again more active. Collectively, 62 % of allBacteroides strains were susceptible to erythromycin (MIC 1 mg/1) and 74 % were susceptible to azithromycin.     

Antibacterial activity of the investigational oral and parenteral cephalosporin BK-218

BK-218 is a novel cephalosporin with a dual route of administration and spectrum of activity most similar to that of second-generation cephalosporins. BK-218 was active againstStreptococcus pneumoniae, Haemophilus influenzae andMoraxella catarrhalis but strains resistant to penicillins had higher MICs. BK-218 had greater activity (8-fold) than cefuroxime or cefaclor against oxacillin-susceptibleStaphylococcus spp. Moderate BK-218 activity was observed againstNeisseria gonorrhoeae and commonly isolatedEnterobacteriaceae such asEscherichia coli (MIC90, 1 mg/l),Klebsiella spp. (MIC90, 2 mg/l), andProteus mirabilis (MIC90, 2 mg/l). The following organisms were generally BK-218-resistant (MIC90, >16 mg/l):Bacteroides fragilis, Pseudomonas spp.,Acinetobacter spp.,Xanthomonas maltophilia, Citrobacter spp.,Enterobacter spp., indole-positiveProteus, Serratia spp., enterococci and oxacillin-resistant staphylococci.     

Susceptibility of European respiratory tract isolates to trovafloxacin, ciprofloxacin, clarithromycin, azithromycin and ampicillin

As part of the Artemis project, 11 500 isolates (3000 from patients with respiratory tract infections) were collected throughout six European countries between 1994 and 1996. Twenty-seven hospitals or laboratories participated in this first phase of the study. The activities of three classes of antimicrobial agents (fluor-oquinolones,-lactam agents, macrolides) are presented for the six most frequently isolated pathogens (Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas aeruginosa, Klebsiella pneumoniae). Overall, trovafloxacin and ciprofloxacin activities were similar forHaemophilus influenzae, Moraxella catarrhalis andKlebsiella pneumoniae isolates. Of theStreptococcus pneumoniae isolates, 6% were resistant to penicillin. Trovafloxacin had the highest activity against theStreptococcus pneumoniae isolates, with a minimum inhibitory concentration of 0.25 mg/l for 90% of isolates (MIC₉₀); all strains tested were susceptible to trovafloxacin. The MIC₉₀ of ciprofloxacin forStreptococcus pneumoniae was 3 mg/l, and overall 52% of the strains were susceptible; 9% were resistant. Azithromycin and clarithromycin exhibited similar activity against all collected pathogens, exceptHaemophilus influenzae. All strains ofHaemophilus influenzae were susceptible to azithromycin compared with 79% for clarithromycin, with respective MIC₉₀s of 2 and 16 mg/l. The data presented demonstrate differences in the susceptibility patterns of six major respiratory tract pathogens in Europe.     

In vitro activity and beta-lactamase stability of the new oral cephalosporin Bay v 3522

The activity of the new oral cephalosporin Bay v 3522 was compared to that of six other beta-lactam agents. Bay v 3522 inhibited methicillin-susceptibleStaphylococcus aureus andStaphylococcus epidermidis at 2 µg/ml, compared to MICs of 8 µg/ml for the other cephalosporins tested. It was more active againstStreptococcus pyogenes (MIC 0.06 µg/ml) than cefuroxime, cefixime, cephalexin and cefaclor. Groups B, C and G streptococci were inhibited at 0.12 µg/ml, while the MIC90 forStreptococcus bovis and viridans streptococci was 0.5 and 2 µg/ml, respectively. The MIC90 for enterococci andListeria monocytogenes was 8 µg/ml.Clostridium perfringens was inhibited by 0.12 µg/ml, but mostBacteroides spp. were resistant. The MIC90 for beta-lactamase positiveEscherichia coli (producing primarily TEM-1) was >64 µg/ml and for beta-lactamase negative strains 16 µg/ml. The MIC90 for high-level beta-lactamase producingKlebsiella pneumoniae was >64 µg/ml versus 4 µg/ml for other isolates. The MIC90 forMoraxella catarrhalis was 2 µg/ml, forHaemophilus influenzae 1 µg/ml, and forNeisseria gonorrhoeae 4 µg/ml.Enterobacter cloacae, Citrobacter freundii, Proteus mirabilis, Providencia spp. andPseudomonas aeruginosa were resistant. Bay v 3522 was destroyed by TEM-1, SHV-1, TEM-3 and P99 beta-lactamases.     

Antibacterial activity and mechanism of action of Monarda punctata essential oil and its main components against common bacterial pathogens in respiratory tract

The aim of the current research work was to study the chemical composition of the essential oil of Monarda punctata along with evaluating the essential oil and its major components for their antibacterial effects against some frequently encountered respiratory infection causing pathogens. Gas chromatographic mass spectrometric analysis revealed the presence of 13 chemical constituents with thymol (75.2%), p-cymene (6.7%), limonene (5.4), and carvacrol (3.5%) as the major constituents. The oil composition was dominated by the oxygenated monoterpenes. Antibacterial activity of the essential oil and its major constituents (thymol, p-cymene, limonene) was evaluated against Streptococcus pyogenes, methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae, Haemophilus influenzae and Escherichia coli. The study revealed that the essential oil and its constituents exhibited a broad spectrum and variable degree of antibacterial activity against different strains. Among the tested strains, Streptococcus pyogenes, Escherichia coli and Streptococcus pneumoniae were the most susceptible bacterial strain showing lowest MIC and MBC values. Methicillin-resistant Staphylococcus aureus was the most resistant bacterial strain to the essential oil treatment showing relatively higher MIC and MBC values. Scanning electron microscopy revealed that the essential oil induced potent and dose-dependent membrane damage in S. pyogenes and MRSA bacterial strains. The reactive oxygen species generated by the Monarda punctata essential oil were identified using 2’, 7’-dichlorofluorescein diacetate (DCFDA).This study indicated that the Monarda punctata essential oil to a great extent and thymol to a lower extent triggered a substantial increase in the ROS levels in S. pyogenes bacterial cultures which ultimately cause membrane damage as revealed by SEM results.     

Comparative in vitro activity of cefpirome and cefepime,two new cephalosporins

In in vitro tests the broad-spectrum cephalosporins cefpirome and cefepime were highly active againstEnterobacteriaceae, although often less so against strains resistant to amoxicillin-clavulanate and ticarcillin-clavulanate, and against most strains ofAcinetobacter spp. andAeromonas hydrophila. They were also active againstPseudomonas aeruginosa, although strains with non-plasmid mediated beta-lactam resistance were sometimes less sensitive. OtherPseudomonas spp. varied in their sensitivity. Both agents were highly active againstHaemophilus influenzae, but beta-lactamase-producingBranhamella catarrhalis were somewhat less sensitive.Neisseria gonorrhoeae were susceptible, although non-beta-lactamase producing penicillin-resistant strains had higher MICs.Gardnerella vaginalis was also susceptible andCampylobacter coli/jejuni usually susceptible. Both antibiotics had good activity againstStaphylococcus aureus and coagulase-negative staphylococci except for methicillin-resistant strains andStaphylococcus haemolyticus which were of borderline sensitivity. All streptococci were sensitive, with the exception of highly penicillin-resistant pneumococci and enterococci against which cefpirome had greater activity than cefepime. Both antibiotics had little useful activity against theBacteroides fragilis group orBacteroides oralis group but were active against most other anaerobes.Clostridium difficile and some otherClostridium species were resistant.     

In vitro activity of RO 15-8074 and RO 19-5247

The in vitro activity of RO 15-8074 (cefetamet) and RO 19-5247, new oral cephalosporins, was compared with that of amoxicillin, cephalexin, cefaclor, cefuroxime and erythromycin against 292 clinical isolates using the agar dilution method. Both RO 15-8074 and RO 19-5247 were very active against Proteus mirabilis, Neisseria gonorrhoeae, Haemophilus influenzae and Streptococcus pyogenes,but less active against Staphylococcus saprophyticus and Enterobacter cloacae.RO 19-5247 was more active than RO 15-8074 against Haemophilus influenzae and Streptococcus viridans.     

In vitro activity of florphenicol

Florphenicol was active at a lower concentration than chloramphenicol against over half of 234 recent clinical bacterial isolates. The majority (98 %) of the isolates were inhibited by florphenicol at a concentration of 8 mg/l or less. Florphenicol was particularly effective against chloramphenicol resistant strains ofHaemophilus influenzae, Klebsiella aerogenes andBacteroides spp. Florphenicol was bacteristatic for salmonellae andEscherichia coli but bactericidal forHaemophilus influenzae. Florphenicol was slightly more active than chloramphenicol againstChlamydia trachomatis, Mycoplasma hominis andMycoplasma pneumoniae but less active againstUreaplasma urealyticum.     

Comparative in vitro activity of the new fluoroquinolone BMY-40062

The results are presented of comparative in vitro susceptibility testing of BMY-40062, a new fluorinated quinolone which contains a tetrabutyl moiety at N-1 and a piperazinyl group at C-7. BMY-40062 inhibited 90 % ofEnterobacteriaceae strains at < 0.5 µg/ml, being either equal in activity to ciprofloxacin or two- to four-fold less active, depending upon the species. BMY-40062 was as active as ciprofloxacin againstPseudomonas aeruginosa (MIC90 0.5 µg/ml) and inhibited most other strains ofPseudomonas species at < 1 µg/ml. It was more active than ciprofloxacin or ofloxacin against hemolytic streptococci andStreptococcus pneumoniae, 90 % of strains being inhibited at < 0.5 µg/ml. MICs increased in the presence of 9 mM Mg²⁺ and at pH 5.5. The frequency of spontaneous mutation was low forEnterobacteriaceae, Pseudomonas aeruginosa andStaphylococcus aureus (10^–10), but repeated exposure to BMY-40062 caused selection of resistant isolates. Clinical isolates ofPseudomonas aeruginosa resistant to ciprofloxacin and ofloxacin were resistant to BMY-40062.     

Post-antibiotic effect of the new streptogramin RP 59500

The post-antibiotic effect (PAE) of RP 59500, a new streptogramin antibiotic, was determined forStaphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Streptococcus pneumoniae, andStreptococcus pyogenes. A 30 min exposure ofStaphylococcus aureus to 5 µg/ml of RP 59500 produced a PAE of 1.9–6.9 h, and a 60 min exposure of 2.5 µg/ml produced a PAE of 3.2–8 h. A 30 min exposure of 5 µg/ml of RP 59500 of coagulase-negative staphylococci produced a PAE of 2.5–7.5 h. PAEs of constitutively erythromycin-resistant staphylococcal isolates were shorter than were the PAEs of highly susceptible isolates. A 30 min exposure to 5 µg/ml of RP 59500 produced a PAE of 7.5–9.5 h forStreptococcus pneumoniae and a PAE of >18 h forStreptococcus pyogenes. RP 59500 produced a longer PAE withStaphylococcus aureus than did vancomycin, oxacillin or erythromycin. These results suggest that RP 59500 may be administered less frequently than would be suggested by its half-life.     

Comparative in vitro activity of lomefloxacin,a new difluoroquinolone

The in vitro activity of lomefloxacin, a new difluoroquinolone, was compared with that of norfloxacin, ciprofloxacin, gentamicin and ceftazidime against a total of 577 recent clinical isolates. MICs were determined by a standard agar dilution procedure, and two inocula (10⁴ and 10⁶ CFU) were used throughout. Lomefloxacin inhibited most species of theEnterobacteriaceae, Staphylococcus aureus (including methicillin-resistant strains) andHaemophilus influenzae at 1 mg/l.Pseudomonas aeruginosa (MIC 90, 4 mg/l) was somewhat more resistant, andPseudomonas maltophilia (MIC 90, 16 mg/l) and theBacteroides fragilis group (MIC 90, 32 mg/l) were considerably more resistant. Overall, lomefloxacin was as active as norfloxacin, but was two- to eightfold less active than ciprofloxacin against most species tested.     

Comparative in vitro activity of the new oral cephalosporin bay v 3522 against aerobic and anaerobic bacteria

The in vitro activity of the new oral cephalosporin Bay v 3522 against 229 aerobic and 330 anaerobic clinical isolates was determined using the agar dilution technique. For comparison, amoxicillin, amoxicillin/clavulanate, cefaclor, cefadroxil, cefuroxime, cephalexin, ciprofloxacin, clindamycin, co-trimoxazole, doxycycline, erythromycin and metronidazole (only anaerobic bacteria) were tested. Bay v 3522 was found to have high activity againstStaphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pneumoniae, Streptococcus pyogenes, Branhamella catarrhalis, Haemophilus influenzae, anaerobic cocci,Propionibacterium acnes, Clostridium perfringens and fusobacteria. When tested against a higher inoculum or using the broth dilution technique, the activity of Bay v 3522 showed little dependence on inoculum size and the bactericidal activity was similar to inhibitory activity in most bacterial groups. Bay v 3522 may be useful in the treatment of skin, soft tissue and respiratory tract infections. Clinical studies are thus warranted.     

In vitro activity of PD 117596-2, a broad-spectrum difluoroquinolone

The activity of PD 117596-2, a novel quinolone, was compared to that of other quinolones, ceftazidime, imipenem and gentamicin. PD 117596-2 inhibited mostEnterobacteriaceae at concentrations <0.25 µg/ml, being equal or superior in activity to ciprofloxacin and 2- to 4-fold more active than ofloxacin. It inhibited ceftazidime-resistantEnterobacter spp.,Citrobacter spp. andSerratia marcescens. The MIC90 forPseudomonas aeruginosa, including strains with imipenem MICs of 8 µg/ml and gentamicin MICs > 16 µg/ml, was 0.25 µg/ml. PD 117596-2 was more active than ciprofloxacin againstPseudomonas cepacia andPseudomonas maltophilia, and it inhibitedNeisseria gonorrhoeae andHaemophilus influenzae at < 0.03 µg/ml. PD 117596-2 inhibited staphylococci at 0.5 µg/ml, being 2-fold superior to other quinolones, and with an MIC of 0.25 µg/ml was more active against group A, B, C and G streptococci andStreptococcus pneumoniae. MICs forBacteroides spp. were 2 µg/ml compared to 8–32 µg/ml for other agents. The frequency of spontaneous resistance was low (< 10^–10). Differences in MICs and MBCs were within one dilution, and there was a minimal effect of inoculum size. Although PD 117596-2 was less active at pH 5.5, MICs were < 0.5 µg/ml.     

Determination of Disk Diffusion and MIC Quality Control Guidelines for GSK2140944, a Novel Bacterial Type II Topoisomerase Inhibitor Antimicrobial Agent

GSK2140944 is a novel bacterial type II topoisomerase inhibitor in development for the treatment of conventional and biothreat pathogens, including Gram-positive pathogens and methicillin-resistant Staphylococcus aureus. This quality control study was performed to establish ranges for selected control strains: S. aureus ATCC 29213 and ATCC 25923, Escherichia coli ATCC 25922, Haemophilus influenzae ATCC 49247, and Streptococcus pneumoniae ATCC 49619. The control ranges will be crucial for the accurate evaluation of GSK2140944 potency as it progresses through clinical trial development.