Comparative susceptibilities of penicillin-resistant pneumococci to co-trimoxazole, vancomycin, rifampicin and fourteen beta-lactam antibiotics

Eighty-four isolates of penicillin-resistant pneumococci were tested for susceptibility to vancomycin, rifampicin, cotrimoxazole, and 14 beta-lactam antibiotics by agar and microbroth dilution methods. Twenty-three were from adult patients with pneumococcal disease, 57 from nasopharingeal carriers (preschool children) and four were resistant South African isolates. For all isolates tested, imipenem (N-formimidoyl thienamycin), rifampicin, ceftriaxone and cefotaxime had the greatest activity ( MIC90 : 0 X 12, 0 X 25, 0 X 5 mg/l, respectively). Cefoxitin and latamoxef were the least active of the drugs studied. The remaining beta-lactams tested had less activity than that of penicillin. All strains were inhibited by 1 mg/l of vancomycin and all but one were resistant to cotrimoxazole. The excellent in-vitro activities of the newer beta-lactam agents (ceftriaxone, cefotaxime and, particularly, imipenem ) and vancomycin against penicillin-resistant pneumococci offer a considerable promise for their use in the treatment of pneumococcal meningitis caused by these strains.     

Susceptibility of pneumococci to 14 beta-lactam agents: comparison of strains resistant, intermediate-resistant, and susceptible to penicillin.

To measure the susceptibility of penicillin-resistant pneumococci to newer beta-lactam agents, we evaluated 54 selected strains recovered from patients with bacteremia or meningitis. Three groups of pneumococci were tested: penicillin-susceptible strains, strains with intermediate penicillin resistance, and penicillin-resistant strains. Minimal inhibitory concentrations of benzyl penicillin, oxacillin, cephalothin, cefamandole, cefoxitin, moxalactam (LY127935), cefotaxime (HR756), piperacillin, pirbenicillin, N-formimidoyl thienamycin (MK0787), cefoperazone (T1551), mezlocillin, azlocillin, and mecillinam were determined. For all groups of pneumococci tested, cefotaxime, and particularly thienamycin, had the greatest activity. Piperacillin, mezlocillin, and azlocillin had activity similar to that of benzyl penicillin. Cefoperazone had less activity than penicillin against strains with penicillin minimal inhibitory concentrations of less than 1 microgram/ml but greater activity than penicillin against strains with greater resistance. Oxacillin, cephalothin, cefamandole, and pirbenicillin all had less activity for each group of pneumococci tested; moxalactam, cefoxitin, and mecillinam had the least activity. The relative differences in susceptibility to penicillin of each group of pneumococci tested were similar for each of the beta-lactam agents tested. The clinical effectiveness of cefotaxime and thienamycin for therapy of disease due to penicillin-resistant pneumococci needs further evaluation, and of particular interest will be the levels of these drugs which can be achieved in cerebrospinal fluid.     

Decreased susceptibility of penicillin-resistant pneumococci to twenty-four beta-lactam antibiotics.

The in-vitro activity of 24 beta-lactam antibiotics was compared using three groups of pneumococci and an agar dilution method comprising 100 penicillin-susceptible, 100 intermediately penicillin-resistant, and 100 highly penicillin-resistant pneumococcal strains. Our results show that intermediately penicillin-resistant and highly penicillin-resistant pneumococci had decreased sensitivity to other beta-lactam agents. According to their relative in-vitro activity, the antimicrobials were classified into three groups. The first group included drugs more active than penicillin (imipenem, meropenem, cefotaxime, ceftriaxone, and cefpirome), which could be useful for the treatment of infections due to penicillin-resistant strains. The second group showed slightly lesser activity than did penicillin, and included: ampicillin, cefdinir, cefuroxime, cefoperazone, azlocillin, mezlocillin, piperacillin, cephalothin, and cefamandole. The remaining antibiotics (oxacillin, cefixime, ceftizoxime, cefetamet, cefaclor, ceftazidime, cefoxitin, cefonicid, and latamoxef) showed poor activity against penicillin-resistant strains, precluding their use for empirical treatment in areas with a high prevalence of penicillin-resistant strains.     

An evaluation of recently developed antibiotics

A number of newer antibiotics, broad-spectrum penicillins and cephalosporins, have been evaluated against Gram-negative rods. The organisms were selected for multi-resistance and transferable resistance factors. None of the broad-spectrum penicillins was much use against most of the organisms. Ceftriaxone, cefotaxime, latamoxef (moxalactam) and N-formimidoyl thienamycin were all highly effective against most multi-resistant Gram-negative bacilli; cefoperazone being inferior to them. Enterobacter and Serratia strains were relatively resistant to all the agents mentioned and against Acinetobacter only N-formimidoyl thienamycin showed much activity. Thus, use of these drugs may increase the proportion of infections due to organisms such as Serratia or Acinetobacter.     

A comparison of the antibacterial activities of N-formimidoyl thienamycin (MK0787) with those of other recently developed beta-lactam derivatives.

The antibacterial activity of N-formimidoyl thienamycin (MK0787) was evaluated in 335 clinical isolates of ampicillin-resistant Enterobacteriaceae, 50 Pseudomonas aeruginosa strains, 28 Acinetobacter spp., 50 Streptococcus faecalis strains, and 7 oxacillin-resistant Staphylococcus aureus strains and was compared with the recently developed beta-lactam antibiotics mezlocillin, cefuroxime, cefazedone, cefoperazone, cefotaxime, and moxalactam. Among the gram-negative bacteria, N-formimidoyl thienamycin was less active than cefotaxime against Klebsiella, Serratia, and Proteus spp. but had comparable activity against Escherichia coli and Enterobacter strains. Activity of the thienamycin derivative was somewhat lower than that of moxalactam against most of the strains and superior to that of mezlocillin, cefuroxime, and cefoperazone. Moreover, N-formimidoyl thienamycin was the most active drug against P. aeruginosa and Acinetobacter spp. and had activity comparable to that of ampicillin against Streptococcus faecalis. N-Formimidoyl thienamycin was bactericidal at concentrations less than twice the minimal inhibitory concentration (MIC) in all gram-negative isolates tested. Oxacillin-resistant staphylococci (MIC of oxacillin, greater than 4 micrograms/ml) were inhibited at low concentrations of the thienamycin derivative (90% MIC, 0.25 micrograms/ml); however, N-formimidoyl thienamycin was not bactericidal at the 90% MIC. The antibacterial activity of N-formimidoyl thienamycin against all of the gram-negative bacilli was observed to be independent of beta-lactamase production.     

Clinical isolates of Streptococcus pneumoniae with different susceptibilities to ceftriaxone and cefotaxime

Ceftriaxone and cefotaxime are extended-spectrum cephalosporins previously demonstrated to possess very similar in vitro activities against Streptococcus pneumoniae. Anecdotal reports of isolates with divergent in vitro susceptibilities to ceftriaxone and cefotaxime have been published. To determine the prevalence of pneumococcal isolates with divergent ceftriaxone and cefotaxime susceptibilities, we tested 1,000 clinical isolates collected by U.S. laboratories in 2001-2002 by broth microdilution and E-test. The percentages of isolates susceptible to ceftriaxone and cefotaxime were significantly different by both broth microdilution (98.6 and 96.6%, respectively; P < 0.05) and E-test (98.3 and 95.8%; P < 0.001). The differences observed were due solely to the activities of the two agents against penicillin-resistant isolates. Twenty-six of 188 penicillin-resistant isolates (13.8%) demonstrated different ceftriaxone and cefotaxime MIC interpretative phenotypes when tested by broth microdilution; 18 isolates were concurrently ceftriaxone susceptible and cefotaxime intermediate, 6 were ceftriaxone intermediate and cefotaxime resistant, and 2 were ceftriaxone susceptible and cefotaxime resistant (1.1% of penicillin-resistant isolates; 0.2% of all isolates tested). Sixteen of the 26 isolates (65%) were from southern U.S. states. The 26 isolates had serogroups and serotypes (6, 9, 14, 19, and 23) commonly associated with penicillin-resistant isolates; SmaI pulsed-field gel electrophoresis identified 18 isolates (69%) dispersed among five subtype groups and 8 isolates that were unrelated to any of the other isolates. We conclude that certain isolates of penicillin-resistant pneumococci are less susceptible to cefotaxime than to ceftriaxone and that these isolates are not the result of the spread of a single clone. Whether such isolates have increased in prevalence over time remains unknown.     

Comparative activities of 13 beta-lactam antibiotics.

An agar dilution method was used to measure the minimal inhibitory concentrations of 13 beta-lactam antibiotics against 868 recent human clinical isolates. Most members of the Enterobacteriaceae were susceptible to cefoperazone, ceftazidime, moxalactam, N-formimidoyl thienamycin, ceftriaxone, and ceftizoxime. Cephalothin was the most active antibiotic against Staphylococcus aureus. Most strains of Pseudomonas aeruginosa were inhibited by ceftazidime, N-formimidoyl thienamycin, and cefsulodin. N-Formimidoyl thienamycin was active against all of the species tested.     

In vitro susceptibility of Campylobacter fetus subsp. jejuni to N-formimidoyl thienamycin, rosaramicin, cefoperazone, and other antimicrobial agents

The activities of 11 antimicrobial agents against 36 strains of Campylobacter fetus subsp. jejuni were studied by a broth microdilution method. All strains were susceptible to 7 of the 11 antimicrobial agents. Of the newer agents tested N-formimidoyl thienamycin (MK0787) and rosaramicin had very good activity, whereas cefotaxime, moxalactam, and cefoperazone had poorer activity.     

Susceptibility of penicillin-sensitive and -resistant strains of Streptococcus pneumoniae to new antimicrobial agents, including daptomycin, teicoplanin, cefpodoxime and quinolones

The minimal inhibitory concentrations (MICs) of nine antibiotics were determined by agar dilution on 123 strains of Streptococcus pneumoniae (65 penicillin sensitive, 42 intermediate resistant and 16 resistant). The antimicrobial agents tested were penicillin G, clindamycin, trospectomycin, daptomycin, teicoplanin, cefpodoxime, ciprofloxacin, ofloxacin and vancomycin. Of these, daptomycin, teicoplanin and vancomycin demonstrated the greatest in-vitro activity against penicillin-resistant strains (MIC90s less than or equal to 0.25 mg/l). Ciprofloxacin, ofloxacin and trospectomycin had equivalent activities unaffected by penicillin-susceptibility (MIC90 of both quinolones 2.0 mg/l, and of trospectomycin 4.0 mg/l). Cefpodoxime was also active in vitro against all strains (MIC90 2.0 mg/l), but MICs increased with increasing penicillin-MICs. Most penicillin-susceptible strains were susceptible to clindamycin, but many penicillin intermediate resistant and resistant strains were resistant to this drug. Results of this study indicate that several newly introduced and experimental antibiotics have potential in the treatment of infections caused by resistant strains of Str. pneumoniae.     

In vitro activity of new beta-lactam antibiotics and other antimicrobial drugs against anaerobic isolates from obstetric and gynecological infections.

The in vitro activities of N-formimidoyl thienamycin, clindamycin, chloramphenicol, metronidazole, cefoperazone, cefotaxime, cefoxitin, moxalactam, penicillin G, and piperacillin were determined against 158 anaerobic bacteria isolated from endometrial wash cultures of women with pelvic infections. In general, N-formimidoyl thienamycin was the most active, with all organisms inhibited by less than or equal to 0.5 microgram/ml. Chloramphenicol, clindamycin, and metronidazole inhibited all organisms by less than or equal to 8 microgram/ml. The penicillins and cephalosporins exhibited variable activity of lesser degrees.     

Beta-lactam antibiotic susceptibility of bacteria responsible for neonatal meningitis

Neonatal meningitis is caused by group B streptococci (GBS), Escherichia coli, and Listeria monocytogenes, in order of frequency. Newly developed cephalosporins with a broad spectrum of activity have altered the therapy of meningitis due to gram-negative bacilli. However, we found that clinical isolates of GBS and L. monocytogenes did not demonstrate uniform susceptibility to beta-lactam antibiotics. Antibiotic potencies for GBS tested were: cefotaxime, penicillin, ceftriaxone, amoxicillin, cefamandole, cephalothin, and moxalactam. N-formimidoyl thienamycin was most active for L. monocytogenes followed by penicillin, cephalothin and chloramphenicol; broad-spectrum cephalosporins were not active against Listeria organisms that were tested. These agents should not be utilized as solitary therapy of meningitis until the organism has been characterized with antibiotic susceptibilities.     

Activity of moxifloxacin and twelve other antimicrobial agents against 216 clinical isolates of Streptococcus pneumoniae

BACKGROUND: An increased incidence of macrolide resistance in penicillin-resistant Streptococcus pneumoniae has been described. METHODS: With this in mind, 216 S. pneumoniae isolates were evaluated for their in vitro susceptibility to a new fluoroquinolone, moxifloxacin, which was compared with penicillin, amoxicillin, cefuroxime, cefotaxime, ceftriaxone, erythromycin, clarithromycin, ciprofloxacin, sparfloxacin, ofloxacin, vancomycin and teicoplanin. A broth microdilution assay was performed in cation- adjusted Mueller-Hinton broth with 5% (v/v) lysed horse blood according to NCCLS guidelines. RESULTS: Erythromycin resistance was observed in all the 22 penicillin-resistant S. pneumoniae (10.1%). All the penicillin- susceptible S. pneumoniae were susceptible to cephalosporins, whereas all the penicillin-resistant ones showed resistance to cefuroxime and only intermediate susceptibility to cefotaxime and ceftriaxone. The 216 tested strains were inhibited by sparfloxacin and moxifloxacin at concentrations of 0.12-0.5 mg/l and 0.06-0.25 mg/l, respectively, regardlesss of whether the strain was penicillin and/or erythromycin resistant. Seven penicillin-resistant strains displayed resistance to ofloxacin. All isolates were susceptible to vancomycin; teicoplanin MIC values ranged from 0.03 to 0.12 mg/l. The excellent in vitro activity of moxifloxacin against S. pneumoniae was not affected by penicillin and/or macrolides. CONCLUSION: Moxifloxacin appears to be a promising choice for the treatment of pneumococcal infections, including situations where therapeutic choices are limited due to penicillin and macrolide resistance.     

Susceptibility of Eikenella corrodens to newer beta-lactam antibiotics.

In vitro susceptibility testing of 28 strains of Eikenella corrodens by the agar dilution technique showed that all strains were uniformly susceptible to penicillin, ticarcillin, cefoxitin, cefotaxime, N-formimidoyl thienamycin, and moxalactam and resistant to clindamycin and cefadroxil. Cefoperazone, piperacillin, and mezlocillin showed good activity, with some strains relatively resistant. Bacampicillin and cefamandole showed relatively poor activity.     

Influence of inoculum size on activity of cefoperazone, cefotaxime, moxalactam, piperacillin, and N-formimidoyl thienamycin (MK0787) against Pseudomonas aeruginosa.

Forty clinical isolates of Pseudomonas aeruginosa were tested for their susceptibility to cefoperazone, cefotaxime, moxalactam, piperacillin, N-formimidoyl thienamycin (MK0787), and gentamicin at three different inocula. At an inoculum of 5 x 10(3) colony-forming units (CFU) per ml, the minimum inhibitory concentrations (in micrograms per milliliter) for 90% of isolates (MIC90) were as follows: gentamicin, 1; N-formimidoyl thienamycin, 2; cefoperazone, 4; piperacillin, 8; moxalactam, 16; and cefotaxime, 16. When the inoculum was increased to 5 x 10(5) CFU/ml, the MIC90 for all drugs tested increased. Among the beta-lactam antibiotics, N-formimidoyl thienamycin and cefoperazone had the lowest MIC90 (8 micrograms/ml) at this inoculum. When the inoculum was increased further to 5 x 10(7) CFU/ml, an MIC90 could be determined only for gentamicin and N-formimidoyl thienamycin (4 and 8 micrograms/ml, respectively). Indeed, the MIC50 for moxalactam, cefotaxime, cefoperazone, and piperacillin was 128 micrograms/ml or more at this inoculum. The minimum bactericidal concentration for 90% of isolates (MBC90) at an inoculum of 5 x 10(5) CFU/ml ranged from 8 micrograms/ml for gentamicin and N-formimidoyl thienamycin to 128 micrograms/ml for cefotaxime. At the highest inoculum, however, whereas the MBC90 for gentamicin and N-formimidoyl thienamycin remained at 8 micrograms/ml, the MBC90 for each of the other drugs was greater than 128 micrograms/ml. N-Formimidoyl thienamycin was the only drug tested for which an MIC100 and MBC100 (MIC and MBC for 100% of isolates) could be determined, and these were not significantly different from the MIC90 and MCB90.     

Susceptibility of gram-positive cocci to various antibiotics, including cefotaxime, moxalactam, and N-formimidoyl thienamycin

The activities of cefotaxime, moxalactam, MK 0787 (N-formimidoyl thienamycin), ampicillin, oxacillin, vancomycin, and clindamycin were compared against gram-positive cocci. MK 0787 was the most active and moxalactam was the least active of these drugs, except against methicillin-resistant Staphylococcus aureus, where vancomycin was most active, and penicillin-resistant pneumococci, where cefotaxime was more active.     

In Vitro Comparison of N-Formimidoyl Thienamycin, Piperacillin, Cefotaxime, and Cefoperazone

The antibacterial activity of N-formimidoyl thienamycin was compared with those of cefotaxime, cefoperazone, and piperacillin against 536 clinical aerobic isolates.     

Penicillin-resistant Streptococcus pneumoniae infections: current trends in epidemiology and antibiotic chemotherapy

The world-wide emergence of penicillin-resistant Streptococcus pneumoniae has led to dilemmas in the management of pneumococcal infections. Furthermore, most penicillin-resistant pneumococci are simultaneously resistant to a wide variety of other antibiotics, including cephalosporins, macrolides and tetracyclines. Epidemiological surveys in Japan demonstrated that 30-50% of clinical isolates were penicillin-insusceptible(MIC: > or = 0.125 microgram/ml). At present time most penicillin-resistant pneumococcal pneumonia cases are well treated with penicillin or cephalosporin, but significant numbers of treatment failures were reported in meningitis patients. Data from healthy mice model of pneumonia clearly showed that carbapenems and vancomycin are more active than cefotaxime or penicillin in high dose. Careful and continuous surveys for trends in antibiotic resistance and clinical impacts of antibiotic-resistant pneumococci are warranted.     

In-vitro activity of ten antimicrobial agents against penicillin-resistant Streptococcus pneumoniae.

The minimum inhibitory concentrations (MICs) of ten antibiotics were determined by the agar dilution method for 40 strains of penicillin-resistant Streptococcus pneumoniae, all of which were clinical isolates from this laboratory. The antibiotics tested were clarithromycin, erythromycin, teicoplanin, vancomycin, ceftriaxone, cefodizime, azithromycin, ramoplanin, ciprofloxacin and MDL 62873. Of these agents, clarithromycin, vancomycin, teicoplanin, ceftriaxone, ramoplanin and MDL 62873 were the most active. The role of these antibiotics as alternatives to penicillin for the treatment of infections caused by penicillin-resistant S. pneumoniae is discussed.     

In vitro activity of cefbuperazone compared with that of other new beta-lactam agents against anaerobic gram-negative bacilli and contribution of beta-lactamase to resistance.

Cefbuperazone was compared with other currently available and investigational antibiotics against 278 clinical isolates of anaerobic gram-negative bacilli by an agar dilution method. Cefbuperazone and cefotetan were equally active against Bacteroides fragilis, with 8% of the organisms tested found to be resistant to 32 micrograms of either drug per ml. Cefoperazone, cefotaxime, ceftriaxone, and cefmetazole were less active against these strains; cefoxitin, moxalactam, piperacillin, clindamycin, and metronidazole were more active. None of the agents were consistently active against any of the other anaerobic gram-negative bacilli except imipenem, for which the minimum concentration required to inhibit 90% of all strains tested was 4 micrograms/ml. A 10,000-fold increase in inoculum size caused an increase in the MIC of ceftriaxone, cefotaxime, and cefoperazone but not of cefbuperazone, cefotetan, or cefoxitin. Investigation of the mechanism of resistance to cephalosporin-like agents demonstrated a correlation between the level of resistance and beta-lactamase activity. Cefbuperazone, cefotetan, and cefoxitin were not hydrolyzed, had lower MICs, and were less affected by changes in inoculum size than were cefotaxime, ceftriaxone, and cefoperazone.     

In-vitro antagonism by N-formimidoyl thienamycin and cefoxitin of second and third generation cephalosporins in Aeromonas hydrophila and Serratia marcescens

Antagonism of beta-lactam antibiotics by second and third generation cephalosporins was studied in 28 clinical strains of Serratia marcescens and Aeromonas hydrophila. Of the antibiotics tested, both cefoxitin and N-formimidoyl thienamycin (N-f-thienamycin) were capable of antagonism in Ser. marcescens (17 of 20) but in Aerom. hydrophila (7 of 8), only cefoxitin induced antagonism. Antagonism was observed to the greatest degree with cefotaxime and cefoperazone; intermediate with cefamandole and latamoxef (moxalactam) and essentially none with N-f-thienamycin. Inducible beta-lactamase was found in all strains of both genera which exhibited antagonism. The induced beta-lactamase showed enhanced inactivation for other antibiotics in only four strains with none occurring in Aeromonas.