Inhibitory and bactericidal activity of cefpirome and cefotaxime against blood culture isolates

Using a broth microtiter dilution method, minimum inhibitory (MIC) and minimum bactericidal concentrations (MBC) were determined for the aminothiazolyl cephalosporins cefpirome and cefotaxime against 436 blood culture isolates. At concentrations of less than or equal to 16 mg/l, cefpirome inhibited 82.3% of the isolates and cefotaxime 66.5%. At the same concentrations, cefpirome killed 60.0% of the isolates and cefotaxime 46.7%. Whereas the MIC values indicated a far better activity of cefpirome than cefotaxime against oxacillin-resistant Staphylococcus aureus, Enterococci and Pseudomonas aeruginosa, the MBC values showed a poor activity of both drugs against these strains. By comparison, cefpirome was the more active agent, covering a similar spectrum to that of cefotaxime with a slight additional activity against oxacillin-susceptible S. aureus and Staphylococcus epidermidis.     

In vitro comparison of cefpirome and four other beta-lactam antibiotics alone and in combination with tobramycin against clinical isolates of Pseudomonas aeruginosa

In vitro susceptibility studies of cefpirome versus cefotaxime, ceftazidime, imipenem, and piperacillin alone and in combination with tobramycin were performed against 153 clinical isolates of Pseudomonas aeruginosa from four medical centers. The minimal inhibitory concentration (MIC) for each antibiotic alone was determined by a standardized dilution method. Antibiotic combination studies were performed using a modified checkerboard technique. Cefpirome alone was more active (MIC90 64 micrograms/ml) than piperacillin (MIC90 128 micrograms/ml) or cefotaxime (MIC90 256 micrograms/ml) but less active than imipenem (MIC90 2 micrograms/ml) or ceftazidime (MIC90 32 micrograms/ml). The addition of tobramycin reduced the MICs of all of the beta-lactam antibiotics except for imipenem. The MIC90 for cefpirome when combined with tobramycin was 8 micrograms/ml compared to 16 micrograms/ml for cefotaxime and piperacillin, 8 micrograms/ml for ceftazidime, and 4 micrograms/ml for imipenem. The combination of tobramycin and cefpirome proved to be additive or synergistic for 82% of the isolates (highest rate) compared to 31% with imipenem (lowest rate). The potent in vitro antipseudomonal activity of cefpirome alone and in combination with an aminoglycoside (tobramycin) suggests that this agent may play a useful role in the therapy of infections due to P. aeruginosa.     

Comparative activity of imipenem (N-formimidoyl thienamycin) on enterococci and its interactions with aminoglycosides

Activity of imipenem (N-formimidoyl thienamycin, ampicillin and vancomycin against 27 Streptococcus faecalis and 5 Str. faecium was determined. Also evaluated were the interactions of imipenem, ampicillin and vancomycin with streptomycin or amikacin or sissomicin. Imipenem showed the most inhibitory activity against Str. faecalis with MIC50 and MIC90 values 0.5 and 2 mg/l respectively, Str. faecium strains were less susceptible to imipenem with MIC50/MIC90 values of 2/16 mg/l. Imipenem showed good bactericidal activity against both groups of strains with MBC50/MBC90 values of 1/4 and 4/16 mg/l respectively. The most favourable interactions (synergy and addition) of imipenem were with streptomycin (72.2%) and sissomicin (53.2%). Combinations containing amikacin were the least favourable. Similar results were obtained with these combinations against Str. faecium.     

Comparison of bactericidal activity of selected beta-lactam antimicrobials against Pseudomonas aeruginosa

The efficacy of ceftazidime, piperacillin, tobramycin and ticarcillin was tested in vitro against 102 clinical isolates of Pseudomonas aeruginosa. The MIC and MBC of each agent alone were determined. In addition, the rate of killing of 27 isolates by each beta-lactam agent was tested both singly and in combination with tobramycin. The concentrations of beta-lactams and of tobramycin were tailored to each organism; these were double the MBC in the case of the beta-lactams and half the MBC for tobramycin. Although 85.2% of isolates were susceptible to piperacillin and only 58.8% were susceptible to ticarcillin, the MBC90 was higher for piperacillin (greater than 256 mg/l) than ticarcillin (199.7 mg/l). The addition of tobramycin in sublethal concentrations increased the rapidity of killing of bacteria.     

In vitro activity of cefepime, a new parenteral cephalosporin, against recent European blood isolates and in comparison with piperacillin/tazobactam

Cefepime, a new parenteral cephalosporin with broad antibacterial spectrum and stability to the hydrolysis to many bacterial beta-lactamases, was tested against recent blood culture isolates (369 strains of gram-negative bacilli and 131 strains of staphylococci) collected in 29 European laboratories by the microdilution method in Mueller-Hinton broth. Cefepime was very active against the gram-negative bacilli (MIC50 less than or equal to 0.016-0.064 mg/l; MIC90 0.064-4 mg/l) and less active against Pseudomonas (MIC50 4 mg/l; MIC90 greater than 16 mg/l) or Acinetobacter (MIC50 and MIC90 greater than 16 mg/l). The staphylococci were also inhibited (MIC50 8 mg/l; MIC90 16 mg/l). Cefepime was very active against bacteria producing different plasmid-encoded beta-lactamases (MIC 0.016-0.5 mg/l). Piperacillin was not active against the latter strains (MIC from 2 to greater than 64 mg/l), but the presence of the beta-lactamase inhibitor tazobactam restored the activity of piperacillin. The bactericidal activity of cefepime and piperacillin/tazobactam against beta-lactamase-producing strains was confirmed by the killing curve technique.     

Comparative efficacies of imipenem-cilastatin and vancomycin in experimental aortic valve endocarditis due to methicillin resistant Staphylococcus aureus

Activities of imipenem and vancomycin against methicillin resistant Staphylococcus aureus (MRSA) were compared in vitro and in a rabbit model of aortic valve endocarditis. Against 25 MRSA clinical isolates, imipenem was bacteriostatic (MIC90/MBC90, mg/l 8/32) in vitro while vancomycin was bactericidal (MIC90/MBC90, mg/l 2/4). Rabbit endocarditis was produced with a MRSA isolate against which both drugs were bactericidal. Imipenem-cilastatin had better efficacy than vancomycin by the following criteria, the number of survivors (9/13 vs 7/13), clearance of bacteraemia (9/9 vs 3/7; P = 0.019), sterility of cardiac vegetations (9/9 vs 1/7; P = 0.001) and sterility of distant organs (8/9 vs 2/7; P = 0.035). Thus, imipenem-cilastatin may be a potentially useful alternative agent to vancomycin in the therapy of MRSA endocarditis in the occasional situations when the drug demonstrates in-vitro bactericidal activity against the pathogen. Efficacy against MRSA strains with higher MBCs remains to be proved.     

Measurement of ampicillin, vancomycin, linezolid and gentamicin activity against enterococcal biofilms

BACKGROUND: Enterococci frequently cause biofilm infections but susceptibility of clinical isolates growing in biofilms has not been investigated. The minimum biofilm eradicating concentration (MBEC) has been suggested as a guide to treatment of biofilm infections. We measured an alternative endpoint, the minimum biofilm inhibitory concentration (MBIC) and compared the results with MIC and MBC. OBJECTIVES: To compare the MIC, MBC and MBIC of ampicillin, vancomycin and linezolid against enterococcal biofilms, to assess the impact of additional gentamicin and correlate findings with clinical outcome. METHODS: MIC and MBC were measured using standard techniques. MBICs were measured using a modification of the Calgary biofilm device method. Fifty-eight enterococcal isolates from episodes of intravascular catheter-related bloodstream infection were tested. RESULTS: Tolerance to ampicillin, vancomycin and linezolid was seen in 93%, 100% and 93% of isolates, respectively. MIC(90)s of ampicillin, vancomycin and linezolid were all 4 mg/L for Enterococcus faecalis isolates. MBC(90)s of ampicillin, vancomycin and linezolid for E. faecalis isolates were 1024, >128 and 2048 mg/L, respectively. MBIC(90)s of ampicillin, vancomycin and linezolid for E. faecalis isolates were 8192, 4096 and 4096 mg/L, respectively. Results for Enterococcus faecium were similar for vancomycin and linezolid but this species was generally more resistant to ampicillin. Adding 10 mg/L gentamicin had a variable effect on MIC, MBC or MBIC, which was not predictable by gentamicin susceptibility on disc testing. CONCLUSIONS: Very high concentrations of ampicillin, vancomycin and linezolid are required to inhibit enterococcal biofilms in vitro. Combining these agents with gentamicin significantly reduced MIC, MBC and MBIC against only a proportion of enterococcal isolates. No correlation between MBIC and outcome was found.     

The in-vitro activity of Ro 17-2301, a new monobactam, compared with other antimicrobial agents

The susceptibility of 554 recent clinical isolates and known resistant bacterial strains to the new monocyclic beta-lactam Ro 17-2301 were studied and compared to that to other beta-lactams (including aztreonam and temocillin) and gentamicin. Ro 17-2301 had a high degree of activity against the Enterobacteriaceae (MIC90 less than or equal to 0.25 mg/l) being similar or slightly more active than aztreonam and ceftazidime. Strains of Acinetobacter spp. (MIC90 16 mg/l). Haemophilus influenzae strains (including beta-lactamase producers) were more susceptible (MIC90 0.5 mg/l) than those of Neisseria gonorrhoeae (MIC90 4 mg/l); against these latter two groups of isolates aztreonam was more active (MIC90 0.12 mg/l). Both aztreonam and Ro 17-2301 had little activity against Gram-positive cocci with the exception of Streptococcus pneumoniae for which the MIC90 of RO 17-2301 was 16 mg/l. Ro 17-2301 had modest activity against Bacteroides fragilis. The MBC of Ro 17-2301 was very similar to the MIC and the addition of human serum had little effect on the amount of the compound. The mean serum protein binding was 26.3%. A study of the penicillin binding protein affinity of Ro 17-2301 in a strain of Escherichia coli showed PBP 3 to be the primary target. The morphological response to exposure to Ro 17-2301 was filamentation followed by lysis after prolonged exposure.     

In-vitro activity of LY146032 against Staphylococcus aureus and S. epidermidis

The antibacterial activity of LY146032, a new cyclic polypeptide, was compared with that of vancomycin against 163 isolates of methicillin-susceptible and methicillin-resistant Staphylococcus aureus and S. epidermidis. The MICs of LY146032 and vancomycin for 90% of the isolates were 1.0 mg/l and 2.0-4.0 mg/l, respectively. Interpretative guidelines for 15 micrograms and 30 micrograms LY146032 discs could not be established because all isolates tested were susceptible to LY146032, on the basis of achievable serum levels. With one exception, MBC to MIC ratios of LY146032 and vancomycin were less than or equal to 2. Inoculum size had minimal effect on ratios. In time-kill studies, both drugs were 99.9% bactericidal at 6 h for four isolates at concentrations four times the MBC or less. No change in LY146032 activity was observed between isogenic pairs that were resistant to other antibiotics. Thus, LY146032 was very active in vitro against all staphylococcal isolates.     

The antimicrobial activity of cefpirome, a new cephalosporin

The activity of the extended spectrum cephalosporin cefpirome (HR 810) was compared with that of other beta-lactams and gentamicin. A total of 524 clinical isolates and strains known to be resistant to certain agents were studied. Against the Enterobacteriaceae, Haemophilus influenzae and Neisseria spp. cefpirome was highly active (MIC90 less than or equal to 0.5 mg/l), generally being as active or slightly more active than ceftazidime and cefotaxime, and 8 to 32 times more active than cefuroxime. Against Pseudomonas aeruginosa cefpirome (MIC90 8 mg/l) was four-fold less active than ceftazidime. Staphylococcus aureus was susceptible to cefpirome (MIC90 2 mg/l) and cefpirome was the only cephalosporin tested with significant activity against Lancefield Group D streptococci. Bacteroides spp. (with the exception of Bact. ureolyticus) were resistant to cefpirome. The compound was bactericidal to all the susceptible strains studied with the exception of Lancefield Group D streptococci. The major target site for cefpirome was PBP 3 and the protein binding was low.     

In vitro activity of teichomycin against isolates of gram-positive bacteria

The in vitro activity of teichomycin has been evaluated against 189 clinical isolates of Staphylococcus aureus, Staphylococcus epidermidis and group D streptococci. Teichomycin was as active as vancomycin, a chemically related antibiotic, on staphylococci and inhibited the in vitro growth of methicillin-resistant strains at the same concentration necessary to inhibit the sensitive ones. Against group D streptococci teichomycin was about three times more active than vancomycin (MIC50 = 0.125 mg/l, MIC90 = 0.4 mg/l). MBC:MIC ratios of both drugs against staphylococci were comparable, but teichomycin had higher bactericidal activity against group D streptococci, as shown also by killing curves. The activity of teichomycin was not significantly affected by variation of pH, even if the maximum activity was achieved at neutral pH, or by different methods of MIC evaluation. The antibiotic seemed more active when tested with a low inoculum (10(3)-10(5)/ml): a two- to threefold increase in MIC was observed at an inoculum of 10(7)/ml. A reduction of the in vitro activity could be shown when Penassay broth was used as culture medium.     

Activity of cefpirome (HR810) against Pseudomonas aeruginosa strains with characterised resistance mechanisms to beta-lactam antibiotics

The activities of cefpirome, cefotaxime, ceftazidime and ceftriaxone were compared against laboratory and clinical strains of Pseudomonas aeruginosa. Isolates with well characterised resistance mechanisms were included. Against carbenicillin-susceptible isolates cefpirome was more active than cefotaxime and ceftriaxone, but less active than ceftazidime. The activity of all four cephalosporins was impaired against isolates that had increased intrinsic (i.e. non-beta-lactamase-mediated) carbenicillin resistance. However, cefpirome and ceftazidime, unlike the other compounds, remained active at less than 16 mg/l against such strains, whereas cefotaxime and ceftriaxone largely failed to do so. Cefpirome maintained full activity against most isolates with plasmid-mediated beta-lactamases, as did the other cephalosporins. Transconjugant studies indicated that only LCR-1 and PSE-2 enzymes could protect P. aeruginosa against cefpirome. Isolates with partial or total chromosomal beta-lactamase derepression were highly resistant to cefotaxime and ceftriaxone (MIC greater than 128 mg/l) but only those with total derepression were resistant (MIC 16-32 mg/l) to cefpirome and ceftazidime, while those with partial derepression were sensitive to 4-8 mg/l of the latter antibiotics. Comparison of cefpirome MICs for totally-derepressed P. aeruginosa and their enzyme-deficient mutants indicated that chromosomal beta-lactamase gave less protection against cefpirome than against other cephalosporins tested. Cefpirome was a weak inducer of class I beta-lactamases. Overall, therefore, cefpirome behaved similarly to ceftazidime against the different P. aeruginosa resistance types.     

Antibacterial properties of investigational, new, and commonly used antibiotics against isolates of Pseudomonas cepacia in Michigan.

Microdilution antimicrobial susceptibility testing was performed with 73 isolates of Pseudomonas cepacia collected from the sputum of patients throughout Michigan with cystic fibrosis. Susceptibility testing was done using new and investigational antibiotics (loracarbef, cefixime, cefpirome, desacetyl-cefotaxime, cefpodoxime, cefmetazole, cefepime, cefprozil, and fleroxacin) and commonly used antibiotics (ceftazidime, mezlocillin, piperacillin, ciprofloxacin, tobramycin, and amikacin). Ceftazidime was the most active antibiotic, and 91.8% of isolates were susceptible to it with MIC50 and MIC90 values of < or = 4 and 16 micrograms/ml, respectively. For mezlocillin, piperacillin, and ciprofloxacin 84.9, 89 and 39.7% of the isolates, respectively, were mostly moderately susceptible. Loracarbef, cefixime, cefprozil, cefmetazole, cefepime, fleroxacin, cefpodoxime, tobramycin, and amikacin did not show activity against P. cepacia. For cefpirome and desacetylcefotaxime 24.7 and 60.3% of the isolates, respectively, were moderately susceptible. Both MIC50 and MIC90 were > 32 micrograms/ml for cefpirome and 32 and > 64 micrograms/ml for desacetylcefotaxime.     

Comparative in-vitro activity of LY146032 a new peptolide, with vancomycin and eight other agents against gram-positive organisms

The in-vitro activity of LY146032, a new biosynthetic peptolide antibiotic, was compared with vancomycin and eight other antibiotics against 190 Gram-positive bacteria. Organisms tested included streptomycin-susceptible and resistant enterococci, nafcillin-susceptible and resistant Staphylococcus aureus, and nafcillin-susceptible and resistant Staph. epidermidis. LY146032 had excellent in-vitro inhibitory and bactericidal activity against nafcillin-susceptible and resistant staphylococci (MIC90 less than or equal to 0.5 mg/l) and against enterococci (MIC90 less than or equal to 2.0 mg/l). LY146032 was more active than vancomycin against the majority of isolated tested. With the exception of trimethoprim-sulphamethoxazole, LY146032 was the most active agent in vitro against enterococci, and was the most active against nafcillin-resistant staphylococci. LY146032 and vancomycin showed a marked increase in MIC when the inoculum was increased from 10(5) to 10(7) cfu/ml. LY146032 and vancomycin were bactericidal at concentrations within two dilutions of the MIC for staphylococci. LY146032 was bactericidal at less than or equal to 8 mg/l for all enterococcal isolates tested.     

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.     

In-vitro teicoplanin-resistance in coagulase-negative staphylococci from patients with endocarditis and from a cardiac surgery unit

Among 31 strains of coagulase-negative staphylococcus (CNS) causing endocarditis in individual patients, 16 had MIC of teicoplanin greater than or equal to 8 mg/l (MIC50, 8; MIC90, 8; MIC range, 0.5-32 mg/l); and 24 had MBC greater than or equal to 16 mg/l (MBC50, 32; MBC90, 64; MBC range, 4-128 mg/l). Greater sensitivity was shown to vancomycin (MIC50, 2; MIC90, 4; MIC range, 1-8 mg/l; MBC50, 2; MBC90, 4; MBC range, 0.5-8 mg/l). Teicoplanin-resistant CNS (MIC, greater than or equal to 8 mg/l) were detected in the anterior nares of two of three patients and six of nine staff, and in the air, of a cardiac surgery unit, and in other series of CNS of clinical origin. The results of in-vitro sensitivity testing of CNS to teicoplanin are dependent on the media and conditions used, and their clinical significance has not been determined. Nevertheless, the findings reported here put in question the use of teicoplanin alone as prophylaxis during valve replacement surgery.     

Susceptibility of non-fermentative gram-negative bacteria to ciprofloxacin, norfloxacin, amifloxacin, pefloxacin and cefpirome

Susceptibility of 340 mainly clinically isolated Gram-negative non-fermenters to ciprofloxacin, norfloxacin, amifloxacin, pefloxacin and cefpirome was determined by agar dilution. Ciprofloxacin was most active, with MIC90s against all organisms ranging between less than 0.125 and 4 mg/l. Norfloxacin, amifloxacin and pefloxacin were active against most strains, with MIC90 ranges (mg/l) of 0.5 - 32, 0.25 - 32 and less than 0.125 - 16, respectively. Cefpirome showed less activity than the quinolones on a weight-for-weight basis with MIC90s ranging from 0.5 to greater than 64 mg/l; only fluorescent pseudomonads and Acinetobacter calcoaceticus biotypes haemolyticus, alcaligenes were uniformly susceptible to cefpirome. The broad-spectrum activity of the four quinolones suggests potential use in therapy of infections caused by non-fermenters; cefpirome should be reserved for infections caused by fluorescent pseudomonads and possibly Acinetobacter spp.     

In vitro activity of daptomycin against 297 staphylococcal isolates

The in vitro activity of daptomycin against 297 clinical isolates of Staphylococcus aureus and S. epidermidis sensu strictu was compared with the activities of cephalothin, dicloxacillin, tobramycin, and vancomycin. Minimal inhibitory concentrations (MICs) were determined by an agar dilution method. Cephalothin and dicloxacillin showed the highest activity against S. aureus on a weight-for-weight basis, all isolates being inhibited by 0.5 mg/l or less of either agent. Cephalothin was somewhat more active against S. epidermidis than was dicloxacillin. Daptomycin and vancomycin exhibited high and similar activity against both S. aureus and S. epidermidis (MIC90% = 1 and 2 mg/l, respectively). Tobramycin was highly active against S. aureus, but the activity against S. epidermidis was greatly variable (MIC range less than or equal to 0.03 - greater than or equal to 16 mg/l). The activity of daptomycin was markedly influenced by the test medium; the MICs were generally 32 times higher when the isolates were tested on Iso-Sensitest agar than on Mueller-Hinton agar. Supplementation of Iso-Sensitest agar with increasing concentrations of calcium potentiated the activity of daptomycin substantially, the results obtained on Iso-Sensitest agar supplemented with 20 mg Ca2+/l being similar to those obtained on Mueller-Hinton agar.     

Antimicrobial tolerance in group C and group G streptococci

The in-vitro activity of various antimicrobial agents against 61 clinical isolates (35 group G streptococci and 26 group C streptococci) was studied. Penicillin, cephalothin and vancomycin were the most active agents with MIC90 values of 0.03, 0.06 and 0.12 mg/l respectively. Tolerance, defined as an MIC to MBC ratio of 32 or greater, was observed in six isolates (four group G--11.4% and two group C-7.7%). Two isolates were tolerant to penicillin alone and one each to cephalothin, vancomycin, latamoxef (moxalactam) and cefotaxime. No cross-tolerance was observed. The addition of gentamicin to the beta-lactam agents and of gentamicin or rifampicin to vancomycin resulted in bactericidal activity. None of the combinations were antagonistic. Our results demonstrate that various bactericidal antimicrobial combinations are available for therapy against tolerant organisms.     

In-vitro susceptibility of Pseudomonas aeruginosa to old and new beta-lactam antibiotics and aminoglycosides

In-vitro, activities of gentamicin, tobramycin, netilmicin, amikacin, cefsulodin, latamoxef (moxalactam), carbenicillin, ticarcillin and piperacillin were compared against 147 randomly selected strains of Pseudomonas aeruginosa. Tobramycin was the most active aminoglycoside (MIC 90:4 mg/l), complete cross resistance with gentamicin (MIC 90:8 mg/l) was observed. Amikacin was the best alternative aminoglycoside (MIC 90:12 mg/l) Netilmicin showed only moderate activity (MIC 90:16 mg/l). Cefsulodin was the most active beta-lactam antibiotic (MIC 90:8 mg/l) but significant cross-resistance was observed with ticarcillin (MIC 90:32 mg/l) and piperacillin (MIC 90:12 micrograms/ml). Carbenicillin was two dilutions less active than ticarcillin, latamoxef showed a good activity (MIC 90:64 mg/l). Having the highest ratio between serum achievable concentration and MIC 90, piperacillin could be the best alternative drug to the aminoglycosides, of the tested antibiotics.