BL-S786, a new parenteral cephalosporin. II. In vitro antimicrobial activity comparison with six related cephalosporins

BL-S786 was compared by in vitro studies with 6 other parenteral cephalosporins (cefamandole, cefazolin, cefoxitin, cephaloridine, cephalothin and cephradine). The following parameters were assessed: Comparative MICs against a wide variety of bacterial isolates, MIC/MBC comparisons and the effect of inoculum size on the MIC. BL-S786 showed the greatest antimicrobial activity against K. pneumoniae, C. diversus and Salmonella species; was equal to cefamandole against E. coli, E. agglomerans and P. mirabilis; and was second to cefamandole against Shigella, E. tarda, C. freundii, E. cloacae, E. aerogenes and the pathogenic Neisseriae. Essentially no activity against Serratia and Pseudomonas species was observed. Compared to the other cephalosporins tested BL-S786 showed poor activity against staphylococci and streptococci. For most species tested, the MBC of the various cephalosporins was the same or within one dilution of their respective MICs. However, for Enterobacter and indole-positive Proteus species, the MBC of BL-S786 and cefamandole was usually larger than or equal to 8-fold higher than the MICs. Cefoxitin, on the other hand, showed little MIC/MBC variations against indole-positive Proteus species. Inoculum size had only a small effect on the MICs against most gram-negative species--in some instances greater than 64-fold increases in MIC resulted by increasing inoculum size from 10(5) to 10(7) organisms per ml.     

Comparison of the in vitro activity of several cephalosporin antibiotics against gram-negative and gram-positive bacteria resistant to cephaloridine

The in vitro activity of each of two oral [cefatrizine (BL-S640), cephalexin] and three parenteral (cefamandole, cefazolin, cephapirin) cephalosporin antibiotics was compared with that of cephalothin against 168 clinical isolates of gram-negative and gram-positive bacteria selected as resistant to 20 mug of cephaloridine per ml on the basis of agar dilution susceptibility test data. Each of the five other cephalosporins inhibited a greater percentage of gram-negative bacillary isolates than did cephalothin or cephaloridine, with minimal inhibitory concentration values ranging 2- to 50-fold lower. Significant differences between minimal inhibitory concentrations of the compounds tested were also observed in tests against strains of Streptococcus faecalis and of methicillin-resistant Staphylococcus aureus. Potential advantages of including more than a single cephalosporin antibiotic in the panel of antibiotics used for routine susceptibility testing, suggested by these observations, are discussed.     

Activity of cefamandole and other cephalosporins against aerobic and anaerobic bacteria

The activity of cefamandole was comparable to that of cephalothin, cefazolin, and cephaloridine against Staphylococcus aureus, Streptococcus pyogenes, and Diplococcus pneumoniae. In contrast, cefamandole was considerably more active than cephalothin, cefazolin, or cephaloridine against gram-negative facultative bacilli, including Haemophilus influenzae, the most striking disparities being noted with indole-positive Proteus and Enterobacter. Bacteroides fragilis was more susceptible to cefoxitin than to cefamandole or cefazolin (median minimal inhibitory concentration, approximately 8, 32, and 32 mug/ml, respectively); cephalothin exhibited still less activity against this species. The majority of other anaerobes were inhibited by relatively low concentrations of all four cephalosporins. The results indicate a potentially valuable role for cefamandole against facultative gram-negative bacilli, including H. influenzae, but no exceptional activity against anaerobes.     

Antimicrobial activity of the new carbapenem biapenem compared to imipenem, meropenem and other broad-spectrum beta-lactam drugs

The in vitro activity of biapenem was compared to that of imipenem, meropenem and other broad-spectrum beta-lactams. A total of 716 isolates from recent cases of clinical septicemia and an additional 137 stock strains possessing known beta-lactamases or other well-characterized resistance mechanisms were tested. The minimal concentrations inhibiting 90% of strains (MIC90) of Enterobacteriaceae species were for biapenem 0.03 to 1 mg/l and for imipenem 0.25 to 2 mg/l. No member of the Enterobacteriaceae was found to be resistant to biapenem. Biapenem and meropenem were the most active drugs against Pseudomonas aeruginosa, with an MIC90 of 1 mg/l. Biapenem was more active than ceftazidime against most gram-negative and gram-positive bacteria tested. Biapenem was as potent as imipenem against anaerobic bacteria (including Bacteroides fragilis), with an MIC90 of 0.25 mg/l. High MICs of biapenem were demonstrated for Xanthomonas maltophilia, oxacillin-resistant Staphylococcus spp. and Enterococcus spp. These species have demonstrated resistance to other carbapenems and to most of the newer cephalosporins. The results of this study, coupled with previously documented favorable qualities of biapenem, endorse further investigation of this broad-spectrum antibacterial agent for clinical use.     

Comparison of the antibacterial activity of nine cephalosporins against Enterobacteriaceae and nonfermentative gram-negative bacilli

The in vitro antibacterial activity of nine cephalosporins (cephalothin, cephaloridine, cephalexin, cefazolin, cefamandole, cefuroxime, cefatrizine, cefoxitin, and cefazaflur) was determined against 344 strains of Enterobacteriaceae and 99 nonfermentative gram-negative bacilli. Cefamandole, cefazaflur, and cefuroxime were the most active cephalosporins against the Enterobacteriaceae (with the exception of Serratia marcescens). However, cefoxitin was the only cephalosporin that inhibited all 30 S. marcescens strains in a concentration of 16 mug/ml and was by far the most active compound against selected cephalothin-resistant strains of Escherichia coli, Klebsiella, and Proteus mirabilis. Acinetobacter spp. were inhibited best by cefuroxime, but none of the cephalosporins had appreciable activity against the Pseudomonas spp.     

In vitro antibacterial activity and susceptibility of cefsulodin, an antipseudomonal cephalosporin, to beta-lactamases

Cefsulodin sodium (SCE-129, CGP-7174/E), active in minimum inhibitory concentrations (MICs) of 0.5 to 64 microgram/ml, was about 16- to 32-fold more active than carbenicillin against Psuedomonas aeruginosa. It was also active against P. diminuta, P. maltophilia, P. paucimobilis, and P. pseudoalcaligenes (MICs of 1 to 32 microgram/ml) but not against other species of Pseudomonas or other gram-negative bacteria. Except with highly carbenicillin-resistant isolates, MICs of cefsulodin for P. aeruginosa were little affected by an increase in the inoculum. With a small inoculum, minimum bactericidal concentrations (MBCs) were the same as or twice the MIC, but increasing the inoculum had a greater effect on the MBC than on the MIC. Cefsulodin was not hydrolyzed by the beta-lactamase induced in P. aeruginosa by growth in the presence of benzylpenicillin and was a poor substrate for beta-lactamases from Enterobacter cloacae and Proteus morganii. However, it was hydrolyzed, albeit slowly, by the beta-lactamase produced by most of our highly carbenicillin-resistant isolates of P. aeruginosa and by TEM-type beta-lactamases.     

Susceptibilities of bacterial isolates from patients with cancer to levofloxacin and other quinolones

The antibacterial activity of levofloxacin was compared with those of ofloxacin and ciprofloxacin against bacterial isolates from patients with cancer. In general, levofloxacin was as active or was twofold more active than ofloxacin and was two- to fourfold less active than ciprofloxacin against most gram-negative pathogens. Against Pseudomonas aeruginosa, ciprofloxacin was the most active agent tested (MIC for 90% of isolates tested, 1.0 microgram/ml). Overall, all three agents had similar activities against gram-positive organisms and were moderately active against methicillin-susceptible Staphylococcus aureus and coagulase-negative staphylococci, Streptococcus species, and Enterococcus species.     

Chemistry of cephalosporin antibiotics. 28. Preparation and biological activity of 3-(substituted)vinyl cephalosporins

3-(Substituted)vinylcephem nuclei have been prepared by the reaction of 3-formylcephem derivatives with stabilized phosphoranes. Appropriate synthetic steps allowed preparation of a series of 3-ethoxycarbonylvinyl- and 3-carboxyvinylcephem derivatives bearing a variety of 7-acylamino functions. The phenoxyacetyl and thiopheneacetyl derivatives of the 3-cyanovinylcephem nucleus were also prepared. Although general gram-positive activity was comparable to cephalothin in many cases, against penicillin G resistant Staphylococcus aureus, the new cephalosporins were of low effectiveness. The 3-(substituted)vinyl cephalosporins had good activity against a number of gram-negative organisms. In some cases, this activity was excellent. The N-acetyl analogs had surprisingly good activity relative to N-acetyl-7-ACA. The phenylmalonoyl side-chain derivatives were shown to have an unusual antibacterial spectrum expansion (relative to previously known cephalosporins) to include activity against Serratia marcescens and Pseudomonas aeruginosa.     

In vitro activity of the new fluoroquinolone CP-99,219

The in vitro activity of the new fluoroquinolone CP-99,219 [7-(3-azabicyclo[3.1.0]hexyl)naphthyridone] was compared with those of four other quinolones against 541 gram-negative, 283 gram-positive, and 70 anaerobic bacterial isolates. CP-99,219 inhibited 90% of many isolates in the family Enterobacteriaceae at a concentration of < or = 0.25 micrograms/ml (range, < 0.008 to 1 microgram/ml), an activity comparable to those of tosufloxacin and sparfloxacin and two times greater than that of temafloxacin. Ninety percent of the Proteus vulgaris, Providencia rettgeri, Providencia stuartii, and Serratia marcescens isolates were inhibited by 0.5 to 2 micrograms of CP-99,219 per ml. CP-99,219 inhibited 90% of the Pseudomonas aeruginosa and Haemophilus influenzae isolates at 1 and 0.015 micrograms/ml, respectively. The compound inhibited methicillin-susceptible Staphylococcus aureus at 0.06 micrograms/ml, whereas a ciprofloxacin concentration of 1 microgram/ml was required to inhibit these organisms. CP-99,219 inhibited 90% of methicillin-resistant S. aureus isolates at a concentration of < or = 4 micrograms/ml, while ciprofloxacin and temafloxacin had MICs against these isolates of > 16 micrograms/ml. Streptococci were inhibited by < or = 0.25 micrograms/ml, an activity comparable to that of tosufloxacin. CP-99,219 was eight times more active than ciprofloxacin against Streptococcus pneumoniae. Bacteroides species were inhibited by CP-99,219 at a concentration of 2 micrograms/ml, whereas inhibition of these species required 4- and 16-microgram/ml concentrations of tosufloxacin and ciprofloxacin, respectively. The MBCs of CP-99,219 ranged from two to four times the MICs, and inoculum size had a minimal effect on MIC. CP-99,219 was active against P. aeruginosa at pH 5.5, with only a fourfold increase in MIC compared with values obtained at pH 7.5. The addition of up to 9 mM Mg(2+) increased the MIC range from 0.03 to 0.06 microgram/ml to 0.12 to 0.5 microgram/ml. In view of its excellent in vitro activity against both gram-positive and gram-negative bacteria, CP-99,219 merits further study to determine it's clinical pharmacologic properties and potential for therapeutic use.     

In vitro activity of rosamicin and erythromycin against a group of nonfermenting gram-negative bacilli

The in vitro inhibitory activity of rosamicin and erythromycin against 283 strains of nonfermenting, gram-negative bacilli was determined by using a broth dilution procedure. Rosamicin demonstrated greater activity than erythromycin against most strains tested. A number of species demonstrated significantly lower minimum inhibitory concentrations to rosamicin and would fall within the therapeutic range of the drug based on current pharmacological data.     

Study on the duration of pyuria after transurethral resection of prostate

Recent Canadian, American and European studies have reported increased ampicillin and trimethoprim/sulfamethoxazole resistance among urinary tract isolates of Escherichia coli. This trend suggests that a reevaluation of first- and second-line therapies for the treatment of community-acquired urinary tract infections is necessary. Mecillinam, a beta-lactam with preferential activity against gram-negative penicillin binding protein 2 (unlike other beta-lactams which preferentially bind gram-negative penicillin binding proteins 1a, 1b or 3), may offer clinically significant activity against ampicillin-resistant and trimethoprim/sulfamethoxazole-resistant E. coli. To test this assertion, the activity of mecillinam was compared with ampicillin, trimethoprim/sulfamethoxazole, nitrofurantoin and ciprofloxacin against 258 consecutive gram-negative urinary tract isolates collected at a Canadian tertiary care hospital. Mecillinam demonstrated significantly better activity than ampicillin and trimethoprim/sulfamethoxazole and significantly less activity than ciprofloxacin and nitrofurantoin against the 258 isolates tested. Against E. coli isolates specifically, mecillinam was significantly more active than ampicillin and trimethoprim/sulfamethoxazole (p < 0. 001) and as active as ciprofloxacin and nitrofurantoin. Mecillinam was active against 91.9% of ampicillin-resistant E. coli and 95.9% of trimethoprim/sulfamethoxazole-resistant E. coli. We conclude that mecillinam should be reevaluated for potential use in the treatment of community-acquired urinary tract infections.     

In vitro activity of fleroxacin against multiresistant gram-negative bacilli isolated from patients with nosocomial infections

In order to evaluate the in vitro activity of fleroxacin against nosocomial gram-negative organisms, 263 multiresistant gram-negative bacilli (203 Enterobacteriaceae and 60 non-fermenting gram-negative bacilli) were isolated from adult patients with nosocomial infections. The different patterns of resistance to eight different antimicrobial agents (ampicillin, carbenicillin, piperacillin, cephalothin, cefamandole, ceftazidime, gentamicin and amikacin) were determined by minimum inhibitory concentration (MIC), using the agar dilution method. The most prevalent multiresistant species isolated were Klebsiella pneumoniae (28.9%), Escherichia coli (24%) and Pseudomonas aeruginosa (12.2%). All these bacterial strains showed three to five resistance patterns to at least three different antibiotics. Resistance to ceftazidime was observed in at least one of the resistance patterns of isolated bacteria. The activity of fleroxacin against multiresistant enteric bacteria was excellent; these strains showed a susceptibility of 79-100%. The susceptibility of P. aeruginosa to antipseudomonal agents was low; however, the activity of fleroxacin against these strains was higher than 60% (MIC < or = 2 microg/ ml), broadly comparable with ciprofloxacin. The resistance to fluoroquinolones detected in this study was no cause for alarm (3%). Consequently, fleroxacin maintains a remarkable activity against Enterobacteriaceae and remains highly active against other gram-negative bacilli. Nevertheless, actions directed at preventing or limiting resistance will be crucial to maintain the viability of fluoroquinolones as important therapeutic agents.     

Antimicrobial activity and spectrum of LB20304, a novel fluoronaphthyridone

Compound LB20304 is a fluoronaphthyridone carboxylic acid with a novel pyrrolidine substituent. This drug was compared with ciprofloxacin, levofloxacin, ofloxacin, and trovafloxacin against over 800 pathogens, most from blood stream infections, by National Committee for Clinical Laboratory Standards reference methods. LB20304 was the most active agent against gram-positive species including strains observed to be resistant to other fluoroquinolones and glycopeptides. The potency of LB20304 (MIC50, 0.03 micrograms/ml) against the Enterobacteriaceae was exceeded only by that of ciprofloxacin (0.015 micrograms/ml). It has limited activity against gram-negative anaerobes.     

Using discordant sib pairs to map loci for qualitative traits with high sibling recurrence risk

Epiroprim (EPM; Ro 11-8958) is a new selective inhibitor of microbial dihydrofolate reductase. EPM displayed excellent activity against staphylococci, enterococci, pneumococci, and streptococci which was considerably better than that of trimethoprim (TMP). EPM was also active against TMP-resistant strains, although the MICs were still relatively high. Its combination with dapsone (DDS) was synergistic and showed as in vitro activity superior to that of the TMP combination with sulfamethoxazole (SMZ). The EPM-DDS (ratio, 1:19) combination inhibited more than 90% of all important gram-positive pathogens at a concentration of 2 + 38 micrograms/ml. Only a few highly TMP-resistant staphylococci and enterococci were not inhibited. EPM was also more active than TMP against Moraxella catarrhalis, Neisseria meningitidis, and Bacteroides spp., but it was less active than TMP against all other gram-negative bacteria tested. Atypical mycobacteria were poorly susceptible to EPM, but the combination with DDS was synergistic and active at concentrations most probably achievable in biological fluids (MICs from 0.25 +/- 4.75 to 4 + 76 micrograms/ml). EPM and the EPM-DDS combination were also highly active against experimental staphylococcal infections in a mouse septicemia model. The combination EPM-DDS has previously been shown to exhibit activity in Pneumocystis carinii and Toxoplasma models and, as shown in the present study, also shows good activity against a broad range of bacteria including many strains resistant to TMP and TMP-SMZ.     

The postantibiotic effect of imipenem: relationship with drug concentration, duration of exposure, and MIC

The postantibiotic effect (PAE) of imipenem against Escherichia coli was measured at a wide variety of drug concentrations and times of exposure. We observed that the area under the concentration-time curve of drug exposure (AUC), the product of time of exposure and concentration of drug, is a much better predictor of the duration of the PAE than either parameter alone. We also measured the PAE of imipenem against strains of gram-positive and gram-negative bacteria for which MICs varied widely. The E50, the AUC required to produce 50% of the maximum PAE, is correlated with the MIC and is independent of species. This may explain why the duration of the PAE differs for bacteria of the same species for which MICs are different.     

Ofloxacin. A reappraisal of its use in the management of genitourinary tract infections

Ofloxacin is an established fluoroquinolone agent which achieves good concentrations in genitourinary tract tissues and fluids. It has good in vitro activity against most Enterobacteriaceae, Staphylococcus saprophyticus, methicillin-susceptible S. aureus, Neisseria gonorrhoeae, Chlamydia trachomatis and Haemophilus ducreyi, intermediate activity against Ureaplasma urealyticum and most enterococci, but limited or no in vitro activity against enterococci, Serratia marcescens, Pseudomonas aeruginosa and many anaerobes. However, high concentrations achieved in the urine ensure its activity against most urinary tract pathogens. Ofloxacin demonstrates consistent efficacy in a broad range of urinary tract infections, achieving bacteriological response rates in excess of 80% in uncomplicated and 70% in complicated infections. The efficacy of ofloxacin was similar to that of all comparators tested including other fluoroquinolones, cephalosporins and cotrimoxazole (trimethoprim/sulfamethoxazole). Ofloxacin is also effective as a single-dose regimen in the treatment of uncomplicated gonorrhoea, as a 7-day regimen in uncomplicated C. trachomatis infections, and as monotherapy in uncomplicated pelvic inflammatory disease (PID). Again, ofloxacin demonstrated similar efficacy to alternative treatments in each type of infection. The availability of an intravenous formulation and near-complete oral bioavailability allow ofloxacin to be administered as a sequential regimen without loss of activity. The tolerability and drug interaction profile of ofloxacin is consistent with that of other fluoroquinolones. The most commonly reported adverse events with ofloxacin are gastrointestinal, neurological and dermatological. It was associated with a lower incidence of photosensitivity and tendinitis and higher incidence of some neurological events than some other fluoroquinolones. Ofloxacin seems to have a lower propensity to interact with xanthines than other fluoroquinolones. Conclusion: ofloxacin has established efficacy in the treatment of a wide variety of urinary tract infections, although, like other fluoroquinolones, it should be used rationally to preserve its activity. Currently, ofloxacin also holds an important place among fluoroquinolones in the treatment of C. trachomatis infections and uncomplicated PID, although its acceptance as monotherapy in PID is likely to depend on clarification of the causative role of anaerobic pathogens in this infection.     

Erythromycin, clarithromycin, and azithromycin: use of frequency distribution curves, scattergrams, and regression analyses to compare in vitro activities and describe cross-resistance

MICs of erythromycin, clarithromycin, and azithromycin for 852 recent clinical isolates were determined by broth microdilution methods. Frequency distribution curves, scattergrams, and regression analyses were used to compare in vitro activities and describe cross-resistance. Clarithromycin was the most active drug against Bacteroides spp. but the least active against Haemophilus influenzae. Azithromycin was most active against H. influenzae, Moraxella catarrhalis, Pasteurella multocida, and Fusobacterium spp. but the least active against Streptococcus spp. and Enterococcus spp. All three drugs had equivalent activities against Staphylococcus spp. and gram-positive anaerobes. None of the three drugs was particularly active against members of the family Enterobacteriaceae or nonfermentative gram-negative bacilli, although concentrations of 4 micrograms of azithromycin per ml inhibited some strains of the family Enterobacteriaceae (particularly Escherichia coli and Citrobacter diversus) and Acinetobacter baumannii. Although relative drug activities varied by organism, organisms relatively susceptible to one were relatively susceptible to all and organisms relatively resistant to one were relatively resistant to all; an exception was fusobacteria, which were usually susceptible only to azithromycin. Cross-susceptibility and cross-resistance were, therefore, the rule (except for Fusobacterium spp.), although the percentage of susceptible organisms could be varied considerably on the basis of the selection of breakpoints.     

Diffusion of antibiotics from acrylic bone-cement in vitro

The diffusion of Fucidin, gentamicin, and clindamycin from acrylic cement was tested in an in vitro system. The activity of Fucidin was very short-lived and only against gram-positive organisms; gentamicin inhibited gram-positive and gram-negative organisms for twenty-two and eleven days respectively; clindamycin had significant action only against gram-positive organisms and retained some activity for fifty-six days. We suggest that the destruction of organisms in the tissues is more likely to be achieved by topical and intravenous administration of antibiotics during the operation than by incorporation of antibiotic in the cement.     

Vancomycin in meningitis caused by penicillin G resistant Streptococcus pneumoniae

We report two cases of penicillin G-resistant pneumococcal meningitis in adults, with clinical and bacteriological failure of amoxicillin and negative or incomplete response to third generation cephalosporins. Meningitis occurred in a man treated for myeloma and in an elderly woman under prolonged intermittent amoxicillin therapy for chronic otitis. Such situations are known as exposing to pneumococcal meningitis and to resistance of the strain involved to penicillin G. Both patients were cured by vancomycin in continuous infusion associated with rifampicin or fosfomycin. Contrary to third generation cephalosporins, which have higher minimal inhibitory concentrations, vancomycin and rifampicin are still fully active against penicillin G-resistant pneumococcal strains. Thus, vancomycin administered in continuous infusion and associated with rifampicin and fosfomycin deserves to be tried as first-line treatment of pneumococcal meningitis in patients at risk of resistance to penicillin G.     

Increasing ciprofloxacin resistance among prevalent urinary tract bacterial isolates in Bangladesh

Ciprofloxacin was evaluated along with other commonly used antibiotics against a total of 425 clinical isolates obtained from urine samples. Samples were collected from outdoor patients from different parts of Dhaka city. Susceptibility tests were done by the standardized disk diffusion method. Among the tested drugs, the percent susceptible rates observed were: ciprofloxacin (74%), ampicillin (29%), cephalexin (54%) and trimethoprim-sulfamethoxazole (43%) tested against all organisms; gentamicin (73%) tested against gram-negative organisms and erythromycin (72%) tested against gram-positive organisms. Ciprofloxacin showed better activity against gram-negative isolates (80%) compared to the other antibiotics. However, strains highly resistant to ciprofloxacin were detected among commonly isolated gram-negative urinary pathogens: Escherichia coli (18%), Klebsiella species (19%) and Pseudomonas species (30%). Overall susceptibility rate for gram-positive cocci was significantly low for all the antibiotics tested including ciprofloxacin (62%). Minimal inhibitory concentration (MIC) of ciprofloxacin was measured for all resistant and susceptible urinary tract infection (UTI) isolates. This study indicates emerging ciprofloxacin resistance among most UTI bacterial pathogens. Increasing resistance against ciprofloxacin demands coordinated monitoring of its activity, and rationale use of the antibiotic in UTI.