E.Hugh Gerlach

Antimicrobial activity and spectrum of rifaximin, a new topical rifamycin derivative

Rifaximin, a rifamycin derivative, was evaluated in vitro to assess its spectrum and potency against a wide variety of bacteria, yeasts, viruses, and parasites. High concentrations of rifaximin were often used to reflect topically achieved levels since this compound is poorly absorbed by oral route. Like rifampin, rifaximin possessed best activity against Staphylococcus spp. (MIC50 < or = 0.015 microgram/ml), Streptococcus spp. (MIC50s, < or = 0.03-0.12 microgram/ml), Enterococcus spp. (MIC50s, 0.25-2 micrograms/ml), Bacillus cereus (MIC50, 0.06 microgram/ml), Moraxella catarrhalis (MIC50, < or = 0.03 microgram/ml), and Haemophilus influenzae (MIC50, 0.25 microgram/ml). Rifaximin demonstrated potential use as a topical agent for bacterial vaginosis by inhibiting Bacteroides bivius-disiens, Gardnerella vaginalis, Lactobacillus spp., and Mobiluncus spp. strains (all MICs < or = 1 microgram/ml). Strains of Haemophilus ducreyi and Neisseria gonorrhoeae (MIC50s, 0.25 microgram/ml) were also inhibited. However, some organisms associated with genital tract infections were rifaximin resistant, for example, Candida spp., herpes virus, mycoplasmas, Trichomonas vaginalis, and Ureaplasma urealyticum. Clinical trials appear warranted using rifaximin topical concentrations that will minimize mutations to rifamycin resistance.

Piperacillin/tazobactam (YTR 830) combination: Comparative antimicrobial activity against 5889 recent aerobic clinical isolates and 60 Bacteroides fragilis group strains

Piperacillin combined with tazobactam (formerly YTR 830) was tested at a ratio of 8:1 against 5889 aerobic isolates and 50 strains from the Bacteroides fragilis group. Imipenem was the most active agent tested against Enterobacteriaceae (99.3% at less than or equal to 4 micrograms/ml), ceftazidime was most effective against nonenteric Gram-negative bacilli (80.7% at less than or equal to 8 micrograms/ml), and piperacillin/tazobactam possessed a superior spectrum against Gram-positive cocci (92.2% at less than or equal to 16/2 micrograms/ml). Against all aerobic strains, piperacillin/tazobactam had a spectrum (90.3% at less than or equal to 16/2 micrograms/ml) comparable to imipenem (93.6% at less than or equal to 4 micrograms/ml) and was distinctly greater than that of ticarcillin/clavulanic acid (73.3% at less than or equal to 16/2 micrograms/ml) and ceftazidime (75.5% at less than or equal to 8 micrograms/ml). Against the B. fragilis group isolates, all piperacillin/tazobactam MICs were less than or equal to 64/8 micrograms/ml. This activity was superior to piperacillin alone (MIC:50, 8-64 micrograms/ml) and cefoxitin (MIC50, 4-64 micrograms/ml). Piperacillin/tazobactam appears to be a promising parenteral antimicrobial combination, with a spectrum effective against a wide variety of clinical pathogens.

Antimicrobial activity of cefpirome an update compared to five third-generation cephalosporins against nearly 6000 recent clinical isolates from five medical centers☆

Cefpirome, cefotaxime, ceftazidime, cefoperazone, ceftizoxime, and ceftriaxone were tested against approximately 6000 fresh clinical isolates from five medical centers. For 3031 strains of Enterobacteriaceae tested, cefpirome consistently had the lowest MIC50s and lowest percentage of resistant strains. Cefpirome was also the most active agent against the 2138 Gram-positive cocci tested; Staphylococcus haemolyticus was uniformly resistant to all agents tested. Against 791 nonenteric Gram-negative bacilli, the activity of cefpirome was most comparable to that of cefoperazone and slightly less active than ceftazidime. Among the current third-generation cephalosporins, cefotaxime and cefoperazone emerged as having better overall balanced activity. Ceftazidime displayed poorest coverage against Enterobacteriaceae and Gram-positive organisms. Ceftizoxime also provided compromised coverage of staphylococci and nonenteric Gram-negative bacilli. Cefpirome remains as active as originally described in 1984 and possesses a slightly wider spectrum of activity against contemporary aerobic pathogens compared to currently marketed third-generation cephalosporins.

Multicenter in vitro evaluation of lomefloxacin (NY-198, SC-47111), including tests against nearly 7,000 bacterial isolates and preliminary recommendations for susceptibility testing

Lomefloxacin (NY-198 or SC-47111) is a difluoro-quinolone derivative having a C-methyl at the 3-position of the piperazine ring, thus minimizing its metabolic alteration in vivo. In our research, its antimicrobial activity was most similar to that of difloxacin, enoxacin, fleroxacin, and norfloxacin but usually less than that of ciprofloxacin and ofloxacin against most species. Lomefloxacin shared cross-resistance with other 4-quinolones but remained very active against ceftazidime-resistant organisms, including stably derepressed beta-lactamase producing Gram-negative bacilli. Lower pH increased the lomefloxacin MICs. MBCs were usually identical to the measured MIC, and the lomefloxacin MICs were not significantly increased by high inoculum concentrations. The Enterobacteriaceae were found to have a very low rate of spontaneous mutation to lomefloxacin resistance (10(-8)-10(-9). In vitro tests by 5-micrograms and 10-micrograms lomefloxacin disks and dilution methods were correlated, and the 10-micrograms disk was recommended for clinical trials using a less than or equal to 4 micrograms/ml susceptible breakpoint. The quality assurance guidelines for dilution tests were determined by a multilaboratory study.

Comparative antimicrobial activity of piperacillin-tazobactam tested against more than 5000 recent clinical isolates from five medical centers a reevaluation after five years

Piperacillin combined with tazobactam at a fixed concentration (4 micrograms/ml) and a ratio (8:1) was tested against 5,029 aerobic isolates and 447 fastidious organisms, including anaerobes. Among the Enterobacteriaceae, > 95% inhibition was shared only by imipenem (99.1% at < or = 4 micrograms/ml), and some newer cephalosporins (95.1% - 99.8% at < or = 8 micrograms/ml), and piperacillin-tazobactam (95.8% at < or = 16/4 micrograms/ml). Piperacillin-tazobactam was the most active agent tested against nonenteric Gram-negative bacilli (93.5% at < or = 8 micrograms/ml). Ampicillin-sulbactam was the most active agent against staphylococci (95.0% at < or = 8 micrograms/ml), followed by imipenem (91.8%), piperacillin-tazobactam (89.3% at < or = 8/4 micrograms/ml), and cefepime (86.2% at < or = 8 micrograms/ml). Against the enterococci, only ampicillin (93.0% at < or = 8 micrograms/ml) with or without sulbactam, piperacillin (91.0% at < or = 16 micrograms/ml) with or without tazobactam, and imipenem (91.0%) had acceptable activity. Piperacillin-tazobactam and imipenem were the most active drugs tested against all aerobic isolates, inhibiting 93.5% of isolates each. Piperacillin-tazobactam inhibited all fastidious isolates tested, including Haemophilus influenzae (MIC90, 0.094/4 micrograms/ml), Moraxella catarrhalis (MIC90, 0.064/4 micrograms/ml), Neisseira gonorrhoeae (MIC90, < or = 0.016/4 micrograms/ml), and Streptococcus pneumoniae (all MICs, < or = 4/4 micrograms/ml). Against the anaerobic isolates, the most broad-spectrum antimicrobial agents tested were imipenem (100.0%), piperacillin-tazobactam (99.5% at < or = 32/4 micrograms/ml), metronidazole (98.4% at < or = 8 micrograms/ml), and ticarcillin-clavulanic acid (95.1% at < or = 32/2 micrograms/ml). These results are nearly identical to a previous study involving the same five medical centers in 1989. Piperacillin-tazobactam appears to remain a highly effective beta-lactamase inhibitor combination with a wide empiric spectrum and potency in teaching hospitals.

Multilaboratory evaluation of the in vitro activity of 13 β-lactam antibiotics against 1474 clinical isolates of aerobic and anaerobic bacteria

The in vitro activity of 13 beta-lactam antibiotics against 1474 recent clinical isolates was evaluated in a multilaboratory study. The most active antibiotic tested in this study was imipenem (98.5% of the strains were susceptible), followed by ticarcillin-clavulanate (91.4%), cefoperazone (90.0%), ceftazidime (87.9%), cefotaxime (87.7%), ceftriaxone (87.0%), ceftizoxime (86.3%), cefotetan (78.5%), ampicillin-sulbactam (77.9%), cefoxitin (73.5%), cefuroxime (70.9%), cefonicid (64.5%), and cefazolin (57.9%).

Cefdinir (FK482), an orally administered cephalosporin in vitro activity comparison against recent clinical isolates from five medical centers and determination of MIC quality control guidelines

Cefdinir, a new oral cephalosporin, was compared to cefaclor, cefadroxil, cefixime, and cefuroxime against greater than 5000 recent aerobic clinical isolates. This multicenter study revealed broad-spectrum cefdinir activity against all Enterobacteriaceae (MIC50s, 0.06-2 micrograms/ml) except Enterobacter cloacae, Morganella morganii, Proteus vulgaris, and Serratia marcescens (MIC50s, greater than or equal to 4 micrograms/ml). Oxacillin-susceptible staphylococci (MIC90s, 0.5-2 micrograms/ml), beta-hemolytic Streptococcus group B (MIC90, 0.06 micrograms/ml), and Acinetobacter lwoffii were also susceptible to cefdinir. The activity of cefdinir was similar to that of cefixime and cefuroxime against Gram-negative organisms and superior to all tested oral cephems when tested against Gram-positive cocci. None of the cephalosporins were active against oxacillin-resistant Staphylococcus spp., enterococci, Pseudomonas spp., or Xanthomonas maltophilia. MIC quality control range guidelines were established for the strains recommended by the National Committee for Clinical Laboratory Standards documents.

RO 23-6240 (AM-833), a new fluoroquinolone: in vitro antimicrobial activity and tentative disk diffusion interpretive criteria.

The susceptibility of over 7000 recent clinical bacterial isolates to RO 23-6240, a new trifluorinated quinolone, was determined at four medical centers. Over 99% of Enterobacteriaceae and 97% of staphylococci were inhibited by less than or equal to 2.0 micrograms/ml of RO 23-6240. Only 71% of Pseudomonas spp. were inhibited by this concentration. Streptococci and enterococci were resistant to RO 23-6240. Clinical isolates of Haemophilus spp., pathogenic Neisseria spp., and Branhamella catarrhalis were inhibited by less than or equal to 0.25 micrograms/ml of RO 23-6240. This drugs antibacterial activity was comparable with that of enoxacin and norfloxacin, but was less than that of ciprofloxacin against most species. Using less than or equal to 2.0 micrograms/ml and greater than or equal to 8.0 micrograms/ml as the susceptible and resistant MIC breakpoints for RO 23-6240, the regression analysis-derived disk diffusion zone diameter breakpoints for the 5 micrograms disk are: Susceptible greater than or equal to 19 mm intermediate 16-18 mm, and resistant less than or equal to 15 mm.

In vitro evaluation of cefixime (FK027, FR17027, CL284635): Spectrum against recent clinical isolates, comparative antimicrobial activity, β-lactamase stability, and preliminary susceptibility testing criteria

Cefixime, a new orally absorbed cephalosporin, was compared by in vitro testing with other oral beta-lactams, including cephalexin, cefaclor, cefuroxime, amoxicillin, and amoxicillin + clavulanate. Enterobacteriaceae were inhibited by lower concentrations of cefixime than any of the reference drugs; 90% and 95% were inhibited by less than or equal to 1.0 and less than or equal to 8.0 micrograms/ml, respectively. Cefixime was the least active among these drugs against staphylococci, with only 31% of 1106 strains inhibited by less than or equal to 8.0 micrograms/ml and less than 1% by less than or equal to 1.0 microgram/ml. Enterococci and pseudomonads were not susceptible to any of the drugs tested. Penicillin-resistant pneumococci were relatively resistant to cefixime, but penicillin-susceptible pneumococci were very susceptible to cefixime. Other streptococci were generally susceptible to all compounds tested, with relative activities of amoxicillin greater than cefaclor and cefuroxime greater than cefixime greater than cephalexin. Cefixime was inactive against Bacteroides species. A slight inoculum effect occurred with cefixime with inocolum concentrations varying from 10(5) to 10(6) colony forming units per milliliter, but this was more marked at 10(7) colony forming units per milliliter. Cefixime was resistant to hydrolysis by seven common beta-lactamases. It inhibited the hydrolysis of nitrocefin only by type 1 cephalosporinases. The disk diffusion zone diameter breakpoints for the 30-micrograms cefixime disk were determined by regression analysis to be greater than or equal to 27 mm (susceptible) and less than or equal to 23 mm (resistant), respectively corresponding to minimal inhibitory concentration breakpoints of less than or equal to 1.0 and greater than or equal to 4.0 micrograms/ml. Because of the high interpretive error rate (13.8%) and the occurrence of these breakpoints on the parabolic portion of the regression curve, we recommend further evaluation of cefixime disks with lower potencies.

Optimal cefotaxime dosing for gram-negative bacteremia: Effective trough serum bactericidal titers and drug concentrations 8 and 12 hr after 1- or 2-gm infusions

Thirteen adult patients (47-81 yr) with gram-negative bacteremia and normal (less than or equal to 1.5 mg/dl) serum creatinines were treated with 1 or 2 gm of cefotaxime every 8 or 12 hr. The infecting organisms were Escherichia coli (9 strains), Klebsiella pneumoniae (2 strains), and one isolate of Salmonella enteritidis and Serratia marcescens. All patients recovered without any serious sequelae. The range of MICs for cefotaxime and desacetyl-cefotaxime were 0.015-0.25 micrograms/ml and 0.015-4.0 micrograms/ml, respectively. The MBC values for cefotaxime and desacetyl-cefotaxime were identical to the MIC values except for two strains. The trough levels of cefotaxime varied from 65.9 to 1.1 micrograms/ml. The serum concentration of desacetyl-cefotaxime varied from 84 to less than 1.0 microgram/ml. All corresponding trough serum inhibitory activities (SIA) were greater than or equal to 1:32. Comparisons of calculated and directly measured serum bactericidal activity (SBA) and SIA results suggest an additive and occasional synergistic benefit of the cefotaxime desacetyl metabolite. This study supports the clinical efficacy and cost-effectiveness of 8- and 12-hr dosing intervals for cefotaxime against bacteremic gram-negative strains having the usual high susceptibility (MICs, less than or equal to 0.25 micrograms/ml) to the newer cephalosporins.