Mary S. Barrett

Comparative Antimicrobial Activity and Kill-Curve Investigations of Novel Ketolide Antimicrobial Agents (HMR 3004 and HMR 3647) Tested against Haemophilus influenzae and Moraxella catarrhalis Strains

The activity of two ketolide compounds, HMR 3004 and 3647, were compared to those of five macrolides, quinupristin/dalfopristin, ciprofloxacin, and ampicillin. The rate of killing for the ketolides was also assessed against Haemophilus influenzae and Moraxella catarrhalis. One hundred H. influenzae and 148 M. catarrhalis isolates were tested using broth microdilution and appropriate growth media. The killing rates of HMR 3004 and 3647 were analyzed using the time-kill method against five strains from each of the two species. Against H. influenzae, the activity of the ketolides (MIC90, 2 or 4 microg/mL) resembled that of azithromycin and quinupristin/dalfopristin and was more active than any tested macrolide. Against M. catarrhalis, HMR 3004 and 3647 were equally potent as azithromycin and clarithromycin (MIC50, 0.06 microg/mL and MIC90, 0.12 microg/mL) and more potent than all other macrolides or quinupristin/dalfopristin. Time-kill kinetic studies revealed that like the macrolide compounds, the ketolides are bacteristatic at or near the MIC for both H. influenzae and M. catarrhalis. This activity can be increased to a bactericidal level if the concentration is increased four- or eightfold the MIC for H. influenzae. In conclusion, HMR 3004 and 3647 have bacteristatic activity against tested respiratory pathogens and may prove to have an important role against macrolide-resistant isolates.

In vitro evaluation of a novel orally administered cephalosporin (Cefditoren) tested against 1249 recent clinical isolates of Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae.

Cefditoren (formerly ME-1206), a new orally administered cephalosporin, was evaluated in vitro against 1249 recently isolated strains of Streptococcus pneumoniae (500 strains), Moraxella catarrhalis (250 strains), and Haemophilus influenzae (499 strains). Reference National Committee for Clinical Laboratory Standards methods were used and the strains were representative for the current rates of beta-lactamase production or penicillin resistance. Cefditoren had MIC50/MIC90 results for Moraxella catarrhalis and Haemophilus influenzae of 0.12/0.5 and < or = 0.008/0.015 microgram/mL, respectively. The pneumococci were consistently twofold to eightfold more susceptible to cefditoren than other oral cephalosporins or penicillins. The MIC90 for penicillin-resistant S. pneumoniae was only 2 micrograms cefditoren/mL, and the highest recorded MIC was 4 micrograms/mL. Cefditoren appears to be a very promising beta-lactam possessing the greatest potency and potential spectrum versus contemporary (1997) respiratory tract pathogens.

BAY 12-8039, a novel fluoroquinolone: Activity against important respiratory tract pathogens

BAY 12-8039 or moxifloxacin is a new 8-methoxyquinolone with documented, improved activity against Gram-positive cocci and anaerobic bacteria. This study tested 1250 commonly isolated respiratory tract pathogens (251 Moraxella catarrhalis, 499 Haemophilus influenzae, 500 Streptococcus pneumoniae) from 1996-1997 clinical infections at more than 30 medical centers. Among the M. catarrhalis strains (81% beta-lactamase-positive) the BAY 12-8039 MIC90 was 0.06 microgram/mL, a potency equal to ofloxacin but less than all other tested fluoroquinolones (ciprofloxacin, clinafloxacin, levofloxacin, sparfloxacin, trovafloxacin). The H. influenzae strains were generally less susceptible to BAY 12-8039 (MIC90, 0.03 microgram/mL) than the tested fluoroquinolones, and the other comparison compounds were less active overall. All S. pneumoniae strains were susceptible to BAY 12-8039 at < or = 0.25 microgram/mL (MIC90, 0.06-0.12 microgram/mL), a value equal-potent to trovafloxacin. This new fluoroquinolone, BAY 12-8039, appears promising for the treatment of community-acquired respiratory tract infections caused by common bacterial species.

The E-Test applied to susceptibility tests of gonococci, multiply-resistant enterococci, and enterobacteriaceae producing potent β-lactamases☆

The E-Test (AB Biodisk, Solna, Sweden), a new and novel approach developed to test antimicrobial susceptibility, was compared with the agar dilution method. A collection of 57 organisms, including those with known resistances to various antimicrobial agents was tested against 15 drugs using the National Committee for Clinical Laboratory Standard (NCCLS) methods. The E-Test quantitative accuracy (+/- 2 log2 dilutions) compared with agar dilution results was 99% for Neisseria gonorrhoeae, 95% for Escherichia coli strains with extended-spectrum beta-lactamases, 100% for Enterobacter-Citrobacter spp. with type-1 stably derepressed enzymes, and 95% for Enterococcus spp. with various drug resistances (penicillins, ciprofloxacin, gentamicin, and vancomycin). The E-Test procedures with these species were easy to perform, reproducible, and quantitatively and qualitatively accurate (89%-100%). The E-Test appears to be an acceptable option for susceptibility testing of these difficult-to-treat, drug-resistant bacterial strains.

Antimicrobial activity of ten macrolide, linsosamine and streptogramin drugs tested againstLegionella species

RP59500, a semisynthetic pristinamycin combination, and 14 other antimicrobial agents were tested against 108Legionella strains. Of the ten macrolide, lincosamine and streptogramin agents tested, the new streptogramin RP59500 ranked seventh in order of activity againstLegionella pneumophila on the basis of MIC90 results as follows: clarithromycin = 14-OH clarithromycin (MIC90 0.12 mg/l) > roxithromycin > erythromycin = tylosin = virginiamycin > RP59500 (MIC90 1 mg/l) = azithromycin > dirithromycin > clindamycin (MIC90 8 mg/l). Of all 14 drugs tested in this study, rifampicin was the most potent with an MIC90 of 0.008 mg/l. In this retrospective study ofLegionella strains (1981–1990 isolates), we observed no trend toward resistance to the agents investigated.

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 (MIC50) value range of less than or equal to 0.03-8 micrograms/ml. The enteric species having the highest MIC90S (greater than or equal to 16 micrograms/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 (MIC90, 1 micrograms/ml) and other staphylococci. Pneumococci, beta-hemolytic streptococci, Haemophilus influenzae, Moraxella catarrhalis, and pathogenic Neisseria spp. (MIC90S, 0.12-0.5 micrograms/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 beta-lactamase hydrolysis by some recently described extended broad spectrum beta-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.

Antimicrobial activity evaluations of two new quinolones, PD127391 (CI-960 and AM-1091) and PD131628

The in vitro activities of PD127391 and the new fluorinated-4-quinolone, PD131628, were compared with each other and with five similar fluoroquinolones (ciprofloxacin, enoxacin, fleroxacin, norfloxacin, and ofloxacin). A total of 844 isolates mainly from recent clinical bacteremias and additional stock strains with well-characterized resistance mechanisms were tested. PD127391 had slightly more activity than PD131628 (90% minimum inhibitory concentration (MIC90)] 0.008-0.12) against the Enterobacteriaceae, but both were two- to fourfold more potent than ciprofloxacin. PD131628 activity was equal to or greater than PD127391 when tested against Pseudomonas aeruginosa. PD127391 showed greatest activity against Bacteroides fragilis group strains (MIC90, 2 micrograms/ml) when compared with PD131628 (MIC90 greater than 8 micrograms/ml). Both PD127391 (MIC90s, 0.015-1.0 micrograms/ml) and PD131628 (MIC90s, 0.03 - greater than 8 micrograms/ml) were more active than ciprofloxacin against Gram-positive organisms. Altering the medium pH, adding divalent cations (magnesium), and increasing the inoculum concentration to 10(6) colony-forming units per spot adversely effected the activity of both PD127391 and PD131628. Resistance selection and mutational rates to resistance were identical to previously studied drugs in their class.

Antimicrobial activities of two investigational fluoroquinolones (CI-960 and E4695) against over 100 Legionella sp. isolates.

The antimicrobial activities of two investigational fluoroquinolones (CI-960 and E4695) were compared with those of five similar compounds and four comparison drugs against 103 strains of Legionella pneumophila and five other Legionella species type strains. When concentrations inhibiting 90% of strains tested (MIC90s) for L. pneumophila were determined, CI-960 and temafloxacin emerged as the most active (0.015 microgram/ml) and were followed in potency by E4695 (0.03 microgram/ml). This activity was two- to fourfold greater than that of the reference drug, ciprofloxacin, and approached that of rifampin (MIC90, 0.008 microgram/ml). All fluoroquinolones studied were more active than erythromycin (MIC90, 0.5 microgram/ml). These two investigational fluoroquinolones appear well suited for further in vivo study of legionellosis therapy.

Clarithromycin in vitro activity enhanced by its major metabolite, 14-hydroxyclarithromycin

14-Hydroxyclarithromycin, an active metabolite of clarithromycin, was compared for antimicrobial activity alone and in combination with the parent compound. The 14-hydroxyclarithromycin potency was comparable to that of clarithromycin, but was more active against Haemophilus influenzae (MIC50, 1 microgram/ml). Combination MICs at pharmacokinetic ratios produced end points equal to the most active component of the combination. However, checkerboard MICs and kill-curve studies suggested enhanced interactive effects. Partial synergy and additive interactions were demonstrated in 96% of strains tested with synergy (partial) most often observed among the Enterococcus faecalis, H. influenzae, and staphylococci. To determine the best in vitro test methods for predicting the value of 14-hydroxyclarithromycin, combination disks or ratio MIC tests may not be practical. A modification of the proposed clarithromycin-susceptible breakpoint (less than or equal to 2 micrograms/ml) upward to less than or equal to 4 micrograms/ml (greater than or equal to 14 mm) was suggested to recognize the additional activity contributed by the 14-hydroxy metabolite. This modification should be applied, limited to susceptibility tests of H. influenzae and possibly the enterococci.

Etest for routine clinical antimicrobial susceptibility testing of rapid-growing mycobacteria isolates

The Etest has become a widely accepted alternative susceptibility-testing method for difficult-to-assess organisms, including rapid-growing Mycobacterium spp. Following an internal validation and literature reviews, the Etest was applied as the routine method for testing Mycobacterium chelonae and Mycobacterium fortuitum isolates. Results from testing 31 strains confirmed the utility of the Etest and the simplicity of the procedure. Mycobacterium chelonae were generally more resistant to all drugs except amikacin (MIC90, 32 micrograms/ml), compared with M. fortuitum strains that were inhibited (MIC50 in the susceptible range) by amikacin (1 microgram/ml), ciprofloxacin (0.032 microgram/ml), doxycycline (0.125 microgram/ml), and trimethoprim-sulfamethoxazole (0.032 microgram/ml). The polymyxin-B disk used as an identification method was confirmed (> or = 10 mm = M. fortuitum). The Etest provides a simple and accurate method for selecting appropriate therapy for infections caused by rapid-growing mycobacteria (a typical case report is presented).