In vitro activities of ertapenem (MK-0826) against recent clinical bacteria collected in Europe and Australia.

Ertapenem (MK-0826, L-749,345) is a 1-beta-methyl carbapenem with a long serum half-life. Its in vitro activity was determined by broth microdilution against 3,478 bacteria from 12 centers in Europe and Australia, with imipenem, cefepime, ceftriaxone, and piperacillin-tazobactam used as comparators. Ertapenem was the most active agent tested against members of the family Enterobacteriaceae, with MICs at which 90% of isolates are inhibited (MIC(90)s) of < or =1 microg/ml for all species. Ertapenem also was more active than imipenem against fastidious gram-negative bacteria and Moraxella spp.; on the other hand, ertapenem was slightly less active than imipenem against streptococci, methicillin-susceptible staphylococci, and anaerobes, but its MIC(90)s for these groups remained < or =0.5 microg/ml. Acinetobacter spp. and Pseudomonas aeruginosa were also much less susceptible to ertapenem than imipenem, and most Enterococcus faecalis strains were resistant. Ertapenem resistance, based on a provisional NCCLS MIC breakpoint of > or =16 microg/ml, was seen in only 3 of 1,611 strains of the family Enterobacteriaceae tested, all of them Enterobacter aerogenes. Resistance was also seen in 2 of 135 anaerobes, comprising 1 Bacteroides fragilis strain and 1 Clostridium difficile strain. Ertapenem breakpoints for streptococci have not been established, but an unofficial susceptibility breakpoint of < or =2 microg/ml was adopted for clinical trials to generate corresponding clinical response data for isolates for which MICs were as high as 2 microg/ml. Of 234 Streptococcus pneumoniae strains tested, 2 required ertapenem MICs of 2 microg/ml and one required an MIC of 4 microg/ml, among 67 non-Streptococcus pyogenes, non-Streptococcus pneumoniae streptococci, single isolates required ertapenem MICs of 2 and 16 microg/ml. These streptococci also had diminished susceptibilities to other beta-lactams, including imipenem as well as ertapenem. The Etest and disk diffusion gave susceptibility test results in good agreement with those of the broth microdilution method for ertapenem.

Norfloxacin, the first of a new class of fluoroquinolone antimicrobials, revisited.

Norfloxacin is the first in a series of new 4-quinolones that have been introduced into medical practice for the treatment of bacterial infections. This totally synthetic compound is a broad spectrum, bactericidal agent that is much more potent than the earlier analogs, i.e. nalixidic acid, pipemidic acid, cinoxacin, rosoxacin, and flumequine, is less likely to select for resistant mutants. While the compound has been used most widely in the treatment of urinary tract infections including pyelonephritis and prostatitis, utility has also been demonstrated in gastrointestinal and ophthalmological infections, gonorrhea, typhoid fever, the typhoid carrier state, as well as in the prophylaxis of traveler's diarrhea, biliary tract infections prior to surgery, and gram-negative bacillary infections in profoundly neutropenic patients.

In vitro activities of antibacterial agents against clinical isolates of Escherichia coli and Klebsiella species from intensive care units.

The susceptibility of 293 cultures of Escherichia coli and 160 cultures of Klebsiella species isolated consecutively from patients in intensive care units at 25 New York area hospitals to four antibiotic agents was determined. Susceptibility testing was performed with the reference agar dilution and broth microdilution procedures. At the minimum inhibitory concentration (MIC) breakpoints (specified in the prescribing information) of less than or equal to 4 micrograms/ml for imipenem, less than or equal to 16 micrograms/ml for cefoxitin, less than or equal to 8 micrograms/ml for ampicillin/sulbactam, and less than or equal to 64 micrograms/ml for ticarcillin/clavulanic acid, all isolates tested were susceptible to imipenem, 98% each of E coli and Klebsiella isolates were susceptible to cefoxitin, 75% and 83% to ampicillin/sulbactam and 96% and 92% to ticarcillin/clavulanic acid. At the recommended National Committee for Clinical Laboratory Standards MIC breakpoints (less than or equal to 4 micrograms/ml for imipenem, less than or equal to 8 micrograms/ml for cefoxitin, less than or equal to 8/4 micrograms/ml for ampicillin/sulbactam, and less than or equal to 16/2 micrograms/ml for ticarcillin/clavulanic acid) all isolates were susceptible to imipenem, 97% of E coli and 98% of Klebsiella isolates were susceptible to cefoxitin, 75% and 83% to ampicillin/sulbactam, and 86% each to ticarcillin/clavulanic acid. Of the 122 isolates with MICs greater than or equal to 128 micrograms/ml to ampicillin, only 19% were susceptible to ampicillin/sulbactam; and of the 150 isolates with MICs greater than 128 micrograms/ml to ticarcillin, 61% were susceptible to ticarcillin/clavulanic acid. The results suggest that, in the antibiotic combinations studied, high levels of penicillinases, capable of significantly affecting the utility of the enzyme inhibitors, are produced.

Comparative in vitro activity of norfloxacin against resistant Neisseria gonorrhoeae.

The in vitro activity of seven antibiotics against 52 isolates of Neisseria gonorrhoeae was determined. Against penicillinase-producing Neisseria gonorrhoeae, ceftriaxone was the most active agent (MIC90 0.015 micrograms/ml), followed by ceftizoxime and norfloxacin (MIC90 0.03-0.125 micrograms/ml). Against spectinomycin-resistant Neisseria gonorrhoeae, the most active agents were ceftizoxime, ceftriaxone and norfloxacin (MIC90 0.015-0.125 micrograms/ml). Ceftizoxime, ceftriaxone and norfloxacin were also the most active agents against tetracycline-resistant Neisseria gonorrhoeae (MIC90 0.06-0.125 micrograms/ml). Overall, the rank order of activity from the most to the least active agent was as follows: ceftizoxime (MIC90 0.015 micrograms/ml); ceftriaxone (MIC90 0.06 micrograms/ml); norfloxacin (MIC90 0.125 micrograms/ml); cefoxitin (MIC90 2 micrograms/ml); tetracycline (MIC90 8 micrograms/ml); penicillin (MIC90 greater than 8 micrograms/ml); and spectinomycin (MIC90 greater than 128 micrograms/ml).

L-658,310, a new injectable cephalosporin. I. In vitro antibacterial properties.

The in vitro antibacterial spectrum of L-658,310, a new semisynthetic cephalosporin, was compared with ceftazidime, aztreonam and piperacillin against a wide variety of randomly selected human clinical isolates. The compound was found to be a broad spectrum bactericidal agent that was more potent than any of the comparison drugs against glucose nonfermenting bacteria. It has especially potent activity against Pseudomonas aeruginosa including multiply-resistant strains. The superior activity of L-658,310 against this group of organisms is attributed to the presence of the dihydroxy substituents on the 2-methylisoindoline moiety of the compound. L-658,310 is not cross-resistant with either imipenem, ceftazidime or piperacillin (representatives of three different classes of beta-lactam compounds) against P. aeruginosa. The lack of cross-resistance with ceftazidime extends to other glucose nonfermenters and several strains of Enterobacteriaceae as well. The compound is active against bacteria known to possess either R-plasmid- or chromosomally-mediated beta-lactamases.

Comparative activity of cefoxitin, ampicillin/sulbactam, and imipenem against clinical isolates of Escherichia coli and Klebsiella pneumoniae.

The in vitro activities of cefoxitin, ampicillin/sulbactam, and imipenem were determined by the standard twofold agar dilution method against 62 strains of Escherichia coli and 40 strains of Klebsiella pneumoniae isolated from patients in intensive care units. Judging from the concentrations required to inhibit at least 90% of the test isolates, imipenem (MIC90 less than or equal to 0.125 micrograms/ml) was markedly more active than cefoxitin (MIC90 = 4 micrograms/ml) and ampicillin/sulbactam (MIC90 = 32 micrograms/ml) against both bacterial genera. Cefoxitin, therefore, was more active than ampicillin/sulbactam against these organisms. Breakpoints specified in the prescribing information are less than or equal to 4 micrograms/ml for imipenem, less than or equal to 16 micrograms/ml for cefoxitin, and less than or equal to 8 micrograms/ml for ampicillin/sulbactam. At these breakpoints all organisms were susceptible to imipenem and cefoxitin, while 73% of E coli and 78% of K pneumoniae were susceptible to ampicillin/sulbactam. At recommended susceptible MIC breakpoints of the National Committee for Clinical Laboratory Standards (less than or equal to 4 micrograms/ml for imipenem, less than or equal to 8 micrograms/ml for cefoxitin, and less than or equal to 4 micrograms/ml for ampicillin/sulbactam) all the isolates tested were susceptible to imipenem, while 98% and 73% of the E coli isolates were susceptible to cefoxitin and ampicillin/sulbactam, respectively, and 100% and 78% of the K pneumoniae isolates were susceptible to cefoxitin and ampicillin/sulbactam, respectively. Approximately 14% of E coli and 17% of K pneumoniae isolates were resistant to ampicillin/sulbactam (MIC greater than or equal to 32/16 micrograms/ml).

Comparative in vitro antimicrobial susceptibilities of a special panel of 74 Bacteroides fragilis group isolates in Wilkins-Chalgren agar with and without sheep blood.

Seventy-four cefoxitin-resistant Bacteroides fragilis group isolates were tested by the serial twofold agar dilution method for susceptibility to imipenem and other agents in medium with and without 5% sheep blood. Imipenem (MIC for 90% of strains tested, 1 microgram/ml) and metronidazole (MIC for 90% of strains tested, 2 micrograms/ml) were the two most active agents. The addition of 5% sheep blood to the medium had little or no effect on the activity of the antibiotics tested.

L-656,575 (OCP-9-176): a novel oxacephem. In vitro activity against aerobic and anaerobic clinical bacterial isolates.

L-656,575 (OCP-9-176) is a novel oxacephem superior to ceftazidime in in vitro activity against clinical isolates of Enterobacter species, methicillin-susceptible Staphylococcus aureus and Staphylococcus epidermidis, and multiply-resistant Pseudomonas aeruginosa. Our results suggest that L-656,575 has a high affinity for penicillin binding proteins of Pseudomonas and may bind preferentially to PBP-3 in this organism. L-656,575 is active against beta-lactamase derepressed Enterobacteriaceae and ceftazidime-resistant P. aeruginosa.

Comparative susceptibilities of Campylobacter pylori to norfloxacin and other agents.

Twenty-one strains of Campylobacter pylori (Campylobacter pyloridis) were tested for susceptibility to norfloxacin and other agents by the serial agar dilution method. Ampicillin (MIC for 90% of isolates [MIC90], 0.016 micrograms/ml) and famotidine (MIC90, greater than 1,024 micrograms/ml) were, respectively, the most and the least active of the agents tested. Norfloxacin (MIC90, 1 microgram/ml) and imipenem (MIC90, 0.125 micrograms/ml) were substantially active against this organism.

Comparative in vitro activity of imipenem against Haemophilus influenzae and Haemophilus parainfluenzae.

A microdilution broth method was used to test 77 clinical isolates of Haemophilus influenzae and Haemophilus parainfluenzae, including beta-lactamase-positive and -negative strains, for susceptibility to ampicillin, chloramphenicol, and imipenem. Except for ampicillin against beta-lactamase-producing strains (MIC for 90% of strains [MIC90], greater than or equal to 128 micrograms/ml), all three antimicrobial agents had comparable in vitro activity (MIC90, less than or equal to 1 microgram/ml) against these bacterial strains.

Tentative interpretive criteria for in vitro antibacterial susceptibility testing with imipenem.

Imipenem is a member of a new class of highly potent beta-lactam antibiotics, carbapenems, with a very broad antibacterial spectrum. This study was undertaken to determine tentative interpretive criteria for in vitro susceptibility testing with 10-micrograms imipenem disks. A careful examination of the zone diameters and the corresponding MICs for 489 clinical isolates by regression-line analysis and the error rate-bounded classification scheme suggested the following guidelines: greater than or equal to 16 mm with an MIC correlate of less than or equal to 4 micrograms/ml for susceptible, 14 to 15 mm (8 micrograms/ml) for moderately susceptible, and less than or equal to 13 mm (greater than or equal to 16 micrograms/ml) for resistant. Lack of cross-resistance between imipenem and broad-spectrum cephalosporins such as cefotaxime and ceftazidime argues against their use as class disks to predict in vitro susceptibility of bacterial species to carbapenems.

Evaluation of three broth disk methods for testing the susceptibility of anaerobic bacteria to imipenem.

Imipenem is a member of a new class of highly potent beta-lactam antibiotics, carbapenems, with an antibacterial spectrum that includes nearly all currently known aerobic and anaerobic bacterial species of clinical significance. Although relatively stable in most standard laboratory media used for antimicrobial susceptibility testing, imipenem undergoes rapid inactivation in thioglycolate broth, a recommended medium for susceptibility testing of anaerobic bacteria by the broth disk method. In the current study, a panel of 36 anaerobic bacteria consisting of 28 clinical isolates and eight quality control strains was used to determine the suitability and accuracy of the broth disk methods with brain heart infusion, Schaedler, and anaerobic broths, in comparison to the reference agar dilution method, for the anaerobic susceptibility testing of imipenem. To achieve single test concentrations of approximately 8, 16, and 64 micrograms/ml for imipenem, cefoxitin, and piperacillin, respectively, which correspond to the MIC breakpoints of the test drugs, four 10-microgram imipenem disks, three 30-microgram cefoxitin disks, and three 100-microgram piperacillin disks were used in 5 ml of broth. The correlation between the reference agar dilution method and each of the three broth disk elution procedures evaluated was excellent, for imipenem (100% agreement) and somewhat less so for cefoxitin and piperacillin. Therefore, brain heart infusion, Schaedler, and anaerobic broths, but not thioglycolate broth, are suitable for anaerobic susceptibility testing of imipenem by the disk elution method.

In vitro antibacterial activity of norfloxacin and other agents against ocular pathogens.

302 clinical isolates representing 16 bacterial species most often implicated in ocular infections were tested in vitro against norfloxacin and a panel of antibacterial agents. On the basis of the 90% minimal inhibitory concentration (MIC90) data, norfloxacin was 4-32 times more active than the next best antimicrobial tested against Citrobacter freundii, Escherichia coli, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Haemophilus influenzae, Neisseria gonorrhoeae and Staphylococcus epidermidis, with overall MIC90 less than or equal to 1 mg/l. Norfloxacin was equal in activity to polymyxin B against Klebsiella pneumoniae (MIC90 = 1 mg/l), and it ranked second to both polymyxin B against Pseudomonas aeruginosa and cotrimoxazole against Staphylococcus aureus, (MIC90 = 2 mg/l in each case). Along with neomycin and cotrimoxazole, norfloxacin (MIC90 = 1 mg/l) ranked second to gentamicin and tetracycline against Moraxella species. Compared to erythromycin (MIC90 less than or equal to 0.125 mg/l), norfloxacin (MIC90 less than or equal to 16 mg/l) was considerably less active against streptococci. Overall, norfloxacin was the most active agent in both potency and antibacterial spectrum against the test organisms. These results suggest the potential use of norfloxacin in the treatment of superficial bacterial infections of the eye.

Effectiveness of the antimicrobial removal device, BACTEC 16B medium, and thiol broth in neutralizing antibacterial activities of imipenem, norfloxacin, and related agents.

The Antimicrobial Removal Device (ARD), BACTEC 16B medium, and Thiol broth were evaluated for their effectiveness in reducing the activity of imipenem (IPM), cefoxitin, moxalactam, and ceftazidime in blood samples. In addition, the capability of the ARD and Thiol broth to bind norfloxacin and the ARD to bind oxolinic and nalidixic acids in urine samples was investigated. At the highest concentrations of the drugs tested (32 micrograms/ml for the four beta-lactams and 256 micrograms/ml for the three quinolinecarboxylic acids), there was at least a 95% reduction in the in vitro activity of each of the antibacterial agents for treated versus untreated samples. Of the compounds tested in the ARD system, the organic acids were more completely removed than were the beta-lactams. The Thiol broth was more effective than the ARD and the BACTEC 16B medium in inactivating imipenem, but it had no effect on the antibacterial activity of norfloxacin.

Multicenter evaluation of the proposed quality control limits and interpretive zone standards for in vitro susceptibility testing with norfloxacin.

A seven-center collaborative study was carried out to evaluate the in vitro performance of the 10 micrograms norfloxacin disks on the basis of previously proposed interpretive susceptibility zone standards and quality control parameters. Of 7,858 clinical isolates tested, 93.2, 4.9, and 1.9% fell into the susceptible, moderately susceptible, and resistant groups, respectively. The quality control data based on a total of 1,368 zone diameter measurements compared quite favorably with the proposed performance limits as follows: Escherichia coli ATCC 25922, 28 to 35 mm versus 28 to 36 mm; Staphylococcus aureus ATCC 25923, 21 to 29 mm versus 17 to 29 mm; and Pseudomonas aeruginosa ATCC 27853, 23 to 27 mm versus 22 to 29 mm.

Tentative interpretive standards for disk diffusion susceptibility testing with norfloxacin (MK-0366, AM-715).

Norfloxacin is a new orally absorbed quinoline derivative structurally related to nalidixic acid but showing an expanded antibacterial spectrum which includes Enterobacteriaceae, Pseudomonas aeruginosa, Streptococcus faecalis, and staphylococci, among other susceptible bacterial species. The application of the regression line and error rate-bounded methods of analysis to the minimal inhibitory concentration and zone size data collected on 413 clinical isolates favored the selection of a 10-micrograms disk content and the adoption of the following interpretive zone size breakpoints for antimicrobial susceptibility testing with norfloxacin: greater than or equal to 17 mm for susceptible, 13 to 16 mm for intermediate, and less than or equal to 12 mm for resistant categories. It is proposed that isolates with minimal inhibitory concentrations of less than or equal to 16 and greater than or equal to 32 micrograms/ml be considered susceptible and resistant to norfloxacin, respectively. Differences in the antibiotic disk contents and in vitro antibacterial spectra and pharmacokinetic properties, together with the much lower rates of cross-resistance reported between norfloxacin and related drugs, strongly argue against the use of the "class disk" concept in this instance and suggest that the 10-micrograms norfloxacin susceptibility disk should be tested separately.

In vitro antibacterial activity of norfloxacin (MK-0366, AM-715) and other agents against gastrointestinal tract pathogens.

A comparison was made of the in vitro activities of norfloxacin and of nine other orally administered antibacterial agents against 180 clinical isolates representing the bacterial species most frequently implicated in infections of the gastrointestinal tract in humans. The 90% minimal inhibitory concentrations showed norfloxacin to be 4, 15, 4, 17, 17, 17, and 33 times more active than the next best compound tested against Campylobacter fetus subsp. jejuni, Escherichia coli, Salmonella spp., Shigella spp., Vibrio cholerae, Vibrio parahaemolyticus, and Yersinia enterocolitica, respectively, with an overall 90% minimal inhibitory concentration of less than or equal to 0.5 micrograms/ml. Norfloxacin was least active against Clostridium difficile (90% minimal inhibitory concentration, 128 micrograms/ml). These results should encourage further evaluation of norfloxacin as a potential chemotherapeutic agent in the treatment of enteric bacterial infections for which antibiotic therapy is indicated.

Quaternary heterocyclylamino beta-lactams. V. L-640,876 treatment of induced enterotoxigenic colibacillosis (scours) in calves and piglets.

A new semisynthetic cephalosporin antibiotic designated L-640,876, 7-beta-(1-benzylpyridinium-4-yl)amino-3-[( (1-methyl-1H-tetrazol-5-yl)thio] methyl)ceph-3-em-4-carboxylate, was highly active in vitro against 110 enteropathogenic strains of Escherichia coli and Salmonella species of animal origin. The MIC90 was 0.125 microgram/ml for the E. coli strains, 2 micrograms/ml for the S. choleraesuis strains and 4 micrograms/ml for the S. typhimurium strains. In colostrum-fed calves infected with E. coli strain B44, L-640,876 administered by gavage at 30 mg/calf (0.67 mg/kg) twice a day for 3 days, starting at 20-hour post-inoculation, eliminated the diarrhea and reduced the mortality from 82% in the infected, nonmedicated calves to 11% in the infected, medicated calves (P less than 0.05). In colostrum-fed piglets infected with E. coli strain P155, L-640,876 administered by gavage at 12.5 or 20 mg/piglet (10 or 16 mg/kg) twice a day for 3 days, starting at 6-hour post-inoculation, eliminated the diarrhea and reduced the mortality from 79% in the infected, nonmedicated to 25% in the infected, medicated piglets (P less than 0.05). Thus, L-640,876 was highly effective in restoring the calves and piglets to good health by eliminating diarrhea and reducing mortality.

Quaternary heterocyclylamino beta-lactams. II. The in vitro antibacterial properties of L-640,876, a new type of beta-lactam antibiotic.

A new semisynthetic cephalosporin antibiotic designated 7-beta-(1-benzylpyridinium-4-yl)-amino-3-[( (1-methyl-1H-tetrazol-5-yl) thio]methyl)ceph-3-em-4-carboxylate (L-640,876) was compared for antibacterial activity in vitro with mecillinam, cefoxitin and cefotaxime. The antibacterial spectrum of L-640,876 and the effect of culture medium composition and inoculum size on activity are most similar to those of mecillinam. In some cases the inoculum effect on MICs correlated with instability of the compound to certain beta-lactamases and in others to the presence of ionized compounds such as sodium chloride in the medium. On balance, L-640,876 was superior to mecillinam in potency and breadth of spectrum.

Comparison of the antibacterial activity of norfloxacin (MK 0366, AM 715), a new organic acid, with that of other orally absorbed chemotherapeutic agents.

425 randomly selected, fresh clinical isolates were tested for susceptibility to norfloxacin and other orally absorbed agents, i.e. amoxicillin, ampicillin, carbenicillin (available commercially as the indanyl ester), cefaclor, cinoxacin, erythromycin, nalidixic acid, penicillin G, tetracycline, trimethoprim and co-trimoxazole. The results have shown norfloxacin to be the most potent agent in vitro against representative members of the family Enterobacteriaceae, Staphylococcus aureus, Pseudomanas aeruginosa, Acinetobacter spp., Neisseria gonorrhoeae and Haemophilus influenzae. Ninety percent of the isolates in these groups of bacteria were inhibited by less than 1 mg/l, 2 mg/l, 8 mg/l, 32 mg/l, 0.06 mg/l and 0.25 mg/l of norfloxacin, respectively. Although norfloxacin inhibited most streptococci and Ureaplasma at a concentration of 8 mg/l or less, penicillin G proved to be the most active against Streptococcus pygenes and Streptococcus pneumoniae; trimethoprim was the most active against Streptococcus faecalis, and tetracycline the most active against Ureaplasma.