In vitro activity of ceftazidime and ceftriaxone

The in vitro susceptibility of 230 clinical isolates, including 55 anaerobic bacteria, was tested with ceftazidime, ceftriaxone, cefotaxime, cefoperazone, moxalactam, cefamandole, cefoxitin, and ticarcillin. Ceftazidime was the most active drug against Pseudomonas aeruginosa and Acinetobacter sp. Against Enterobacteriaceae, ceftazidime and ceftriaxone were similar to cefotaxime, moxalactam, and cefoperazone and more active than cefamandole, cefoxitin, and ticarcillin. Cefoxitin and moxalactam were significantly more active against Bacteroides fragilis than were the other beta-lactam drugs. Against Staphylococcus aureus, ceftriaxone showed moderate activity, while ceftazidime was relatively inactive. These results indicate a potential role for ceftazidime and ceftriaxone against infections involving facultative and aerobic gram-negative bacilli.     

Susceptibilities of 200 penicillin-susceptible and -resistant pneumococci to piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, ceftazidime, and ceftriaxone.

MICs of eight beta-lactams (piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, ceftazidime, and ceftriaxone) were determined by agar dilution against 64 penicillin-susceptible, 70 intermediately penicillin-resistant, and 66 fully penicillin-resistant pneumococci. The MICs of piperacillin with and without tazobactam for 90% of the susceptible, intermediately resistant, and resistant strains tested (MIC90s) were < or = 0.064, 2.0, and 4.0 micrograms/ml, respectively. By comparison, those of ampicillin with and without sulbactam were 0.125, 2.0, and 4.0 micrograms/ml and those of ceftriaxone were < or = 0.064, 1.0, and 2.0 micrograms/ml, respectively. Strains were less susceptible to ticarcillin with and without clavulanate (MIC90s, 2.0, 64.0, and 128.0 micrograms/ml) and ceftazidime (MIC90s, 1.0, 8.0, and 32.0 micrograms/ml).     

The effects of ions on antibacterial activity of ofloxacin and ceftriaxone.

MIC and MBC values of ofloxacin and ceftriaxone were investigated against Staphylococcus aureus in MHB and MHB containing additional Mg2+, Al3+, Fe3+, Ca2+, Zn2+, Cu2+. The addition of Mg2+, Al3+, Fe3+ increased the MIC and MBC of ofloxacin and the MBC of ceftriaxone. However, the addition of these cations did not change the MIC of ceftriaxone. Our findings suggest that these interactions might be due to the formation of chelates between metal ions and antibiotics. These results also indicate that some cations may have an important role in the antibacterial activity of antibiotics.     

In vitro antibacterial activity of the combination of clindamycin and ceftazidime.

A total of 49 anaerobic and 52 aerobic or facultative bacteria were tested for their susceptibilities to clindamycin and ceftazidime alone and in combination. Synergy was noted for 11 strains, whereas antagonism was not detected. The combination of clindamycin and ceftazidime may prove to be useful for the treatment of severe mixed infections caused by anaerobes and aerobes or facultative bacteria.     

The in-vitro activity of piperacillin/tazobactam, ciprofloxacin, ceftazidime and imipenem against multiple resistant gram-negative bacteria

One hundred and fifty Gram-negative bacterial strains including respiratory pathogens, such as Haemophilus influenzae and Branhamella catarrhalis, and Enterobacteriaceae with known resistance to beta-lactam and other antibiotics were tested in vitro for sensitivity to piperacillin, piperacillin/tazobactam (ratio 8:1), ceftazidime, ciprofloxacin and imipenem. A 16-fold or greater reduction in the MIC90 of piperacillin was achieved by the addition of tazobactam, in the respiratory pathogens, thus bringing them within the susceptible range. Among the Enterobacteriaceae, a 32-fold or greater reduction in the MIC90 was found for Providencia stuartii, Proteus mirabilis and Aeromonas hydrophila. When compared with the other three antimicrobials, the combination was found to be active against fewer species of multiply resistant Enterobacteriaceae, but equally effective against H. influenzae and B. catarrhalis.     

Empiric therapy for secondary peritonitis: a pharmacodynamic analysis of cefepime, ceftazidime, ceftriaxone, imipenem, levofloxacin, piperacillin/tazobactam, and tigecycline using Monte Carlo simulation

BACKGROUND: Inappropriate antibiotic therapy (ie, the selection of an empiric agent without activity against the responsible pathogen) of secondary peritonitis may result in poor patient outcomes. The selection of an appropriate agent can be challenging because of the emerging resistance of target organisms to commonly prescribed antibiotics. OBJECTIVE: The aim of this study was to perform a pharmacodynamic analysis, using recent global surveillance data, of commonly prescribed antibiotic agents and a newer agent, tigecycline, indicated in 2005 for the treatment of complicated intra-abdominal infections, to determine their probability for achieving microbiologic success against aerobic bacteria associated with secondary peritonitis. METHODS: A 2-compartment model was constructed using pharmacokinetic data from critically ill patients and global surveillance data on MIC distributions for microorganisms encountered in secondary peritonitis. A Monte Carlo simulation of the modeled data was performed to determine drug-appropriate pharmacodynamic end points, including free-drug time above the MIC, steady-state concentration above the MIC, and AUC/MIC ratios. A cumulative fraction of response (CFR) against aerobic bacteria involved in secondary peritonitis was calculated for cefepime, ceftazidime, ceftriaxone, imipenem, levofloxacin, pip eracillin/tazobactam, and tigecycline. A CFR > or =90% was considered microbiologic success. The following treatment regimens, administered as 30-minute N infusions, were examined: cefepime 1 and 2 g q12h, ceftazidime 1 and 2 g q8h, ceftriaxone 1 and 2 g q24h, imipenem 500 mg q6h, levofloxacin 750 mg q24h, pip eracillin/tazobactam 3.375 g q6h, and tigecycline 50 mg q12h, after a loading dose of 100 mg. RESULTS: A CFR > or =90% against nonenterococcal bacteria was predicted for imipenem 500 mg q6h (96.8%), cefepime 2 and 1 g q12h (95.3% and 92.4%, respectively), ceftazidime 2 g q8h (94.2%), and piperacillin/tazobactam 3.375 g q6h (91.2%). A CFR of 84.5% was predicted for tigecycline 50 mg q12h. Ceftriaxone and levofloxacin were predicted to have a CFR <80%. When enterococci were included in the model, the predicted CFRs for imipenem, piperacillin/tazobactam, and tigecycline were 93.4%, 88.4%, and 86.7%, respectively. CONCLUSIONS:: MIC distribution and pathogen prevalence strongly influence the likelihood of microbiological success in secondary peritonitis; therefore, decisions regarding empiric therapy should consider local epidemiology. Using current global data, the following regimens are adequate choices if Enterococcus is not targeted: Combination therapy (with metronidazole) using cefepime 1 g or 2 g q12h, or ceftazidime 2 g q8h; or monotherapy with imipenem 500 mg q6h or piperacillin-tazobactam 3.375 g q6h. When Enterococcus is included in the epidemiologic mix, imipenem, piperacillin/tazobactam, and tigecycline all appear to be viable monotherapeutic choices.     

Effect of concomitant administration of piperacillin on the dispositions of netilmicin and tobramycin in patients with end-stage renal disease.

The effect of piperacillin administration on the dispositions of netilmicin and tobramycin was assessed in 12 chronic hemodialysis patients. Six subjects each received netilmicin (2 mg/kg) or tobramycin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Subjects also received a single dose of piperacillin (4 g) on a separate occasion. The serum concentration-versus-time profiles of netilmicin and tobramycin were biexponential. The terminal elimination half-life (t1/2 beta) of tobramycin was markedly reduced (59.62 +/- 25.18 [mean +/- standard deviation] versus 24.71 +/- 5.41 h) and total body clearance (CLP) was significantly increased in the presence of piperacillin (3.45 +/- 1.61 versus 7.16 +/- 1.64 ml/min). In contrast, the t1/2 beta (41.80 +/- 13.24 versus 40.07 +/- 10.37 h) and CLP (5.11 +/- 2.15 versus 5.55 +/- 2.32 ml/min) of netilmicin were not significantly altered when netilmicin was administered in combination with piperacillin. No change in the central or steady-state volume of distribution of netilmicin or tobramycin was observed. The disposition of piperacillin in hemodialysis patients was not altered in the presence of either aminoglycoside antibiotic. Although no adjustment in netilmicin dosing is required, tobramycin should be administered more frequently when given concomitantly with piperacillin to hemodialysis patients to avoid prolonged periods of subtherapeutic concentrations.     

Effect of concentration and time upon inactivation of tobramycin, gentamicin, netilmicin and amikacin by azlocillin, carbenicillin, mecillinam, mezlocillin and piperacillin

Carbenicillin and ticarcillin have been shown to inactivate aminoglycoside antibiotics. This study evaluated the effect of time upon in vitro interaction between mixtures of four aminoglycoside antibiotics at two concentrations with azlocillin, mecillinam, mezlocillin, piperacillin and carbenicillin at three concentrations. By linear regression analysis, the inactivation of each aminoglycoside antibiotic was shown to be directly proportional to the concentration of the semisynthetic penicillin. Aminoglycoside inactivation was greater after 72 hr of incubation with the penicillins than after 24 hr of incubation. Inactivation by each semisynthetic penicillin was greater for tobramycin and gentamicin than for netilmicin and amikacin, especially at higher concentrations of the penicillins. At concentrations of 500 microgram/ml, significantly less inactivation of amikacin occurred when compared to netilmicin. There was little difference in inactivation of a specific aminoglycoside by any of the semisynthetic penicillin antibiotics. No significant change in aminoglycoside activity occurred when the aminoglycosides were stored with the semisynthetic penicillin derivatives at -70 degrees C for 30 days. Conclusions from this study are: 1) serum specimens containing aminoglycoside-penicillin combinations should be tested immediately or frozen before antibiotic assay and 2) aminoglycoside inactivation by the newer semisynthetic penicillins may be important in patients with renal failure who are receiving these antimicrobial agents.     

Post-antibiotic effect of ceftazidime, ciprofloxacin, imipenem, piperacillin and tobramycin for Pseudomonas cepacia.

The post-antibiotic effects (PAE) of ceftazidime, ciprofloxacin, imipenem, piperacillin and tobramycin were studied for ten strains of Pseudomonas cepacia isolated from patients with cystic fibrosis. Antibiotic concentrations used for exposure were either the MIC of each agent for the sensitive isolates or the recommended sensitivity breakpoint concentrations for the resistant isolates. After 2 h of exposure, cultures were rapidly diluted 1000-fold to eliminate the antibiotic. Out of the ten isolates, there were eight sensitive to ceftazidime, six to ciprofloxacin, six to imipenem, nine to piperacillin and five to tobramycin. All antibiotics tested demonstrated PAE for some isolates of P. cepacia, however, each antibiotic failed to produce a PAE for at least one isolate. The mean PAE was 1.35 h for ceftazidime, 2.38 h for ciprofloxacin, 2.39 h for imipenem, 2.16 h for piperacillin and 1.77 h for tobramycin. Imipenem demonstrated PAE of > or = 0.5 h for all sensitive isolates tested; ceftazidime, piperacillin, ciprofloxacin and tobramycin demonstrated PAE of > or = 0.5 h for 6/8, 8/9, 5/6 and 2/5 sensitive isolates, respectively. These data indicate that several antibiotics have significant (> or = 0.5 h) PAE for isolates of P. cepacia.     

In vitro studies of the synergism of piperacillin and netilmicin against blood culture isolates

The purpose of this study was to evaluate the in vitro synergism between piperacillin and netilmicin against microorganisms isolated from Danish patients with septicemia and to examine the influence of inactivation of piperacillin among these bacteria on the synergy results. A total of 132 stains was examined: Escherichia coli 20, indole-positive Proteus 17, Klebsiella pneumoniae 18, Enterobacter cloacae 20, Pseudomonas aeruginosa 20, Staphylococcus aureus 20, and coagulase-negative staphylococci 17. Synergy testing was performed by checkerboard titration in microtiter trays. The ability of the strains to inactivate piperacillin was examined by the clover-leaf test. Synergism was found for 52% of the strains and partial synergism for 32%. Antagonism was not found. Of the piperacillin-resistant strains synergism could be demonstrated in 80% compared with 33% of the piperacillin-susceptible strains (p less than 0.001). No significant correlation was seen between the results of the synergy test and the results of the susceptibility test to netilmicin. The frequency of piperacillin inactivation according to the clover-leaf test was significantly higher among the strains with synergism than among all the others (p less than 0.02). The combination of piperacillin and netilmicin gave good results concerning the in vitro synergism. This synergism was probably sometimes caused by netilmicin disturbing the bacterial production of piperacillin-inactivating proteins.     

Effect of physical activity on the pharmacokinetics of ceftazidime in mice

BACKGROUND: The aim of the present work was to assess comparatively the pharmacokinetic profile of ceftazidime (CAZ) in trained and non-trained mice. METHODS: The study was performed on 256 mice divided at random into four groups: long-term physically trained mice with (E1a) and without (E1b) physical activity prior to the administration of CAZ, and untrained mice with (E2a) and without (E2b) physical activity prior to the administration of the antibiotic. CAZ was administered intramuscularly (25 mg/kg) to all mice, and blood samples were obtained at different time points. The plasma concentrations of CAZ were determined by HPLC and analyzed by non-compartmental models. RESULTS: The area under the curves in groups E1a and E2a (27.3 and 22.9 microg x ml(-1) x h, respectively) were different compared to the other groups [(E1b) = 11.1 and (E2b) = 15.6 microg x ml(-1) x h; p < 0.05]. Differences were observed between the concentration-time of CAZ in E1a compared to E1b, E1a versus E2a, E1a versus E2b, E1b versus E2a and E1b versus E2b (p < 0.05). CONCLUSION: Physical activity performed prior to CAZ administration modified the pharmacokinetic profile of the drug administered to mice.     

Inhibition of beta-lactamases by tazobactam and in-vitro antibacterial activity of tazobactam combined with piperacillin

The in-vitro synergistic activity of tazobactam, a new beta-lactamase inhibitor, combined with piperacillin was tested against various beta-lactamase-producing strains. The beta-lactamase inhibitory activity of tazobactam against various known types of beta-lactamase was also tested in comparison with clavulanic acid or sulbactam. Tazobactam caused a remarkable reduction of the piperacillin MICs for penicillinase- and oxyiminocephalosporinase-producing strains and also showed a moderate synergistic effect against cephalosporinase-producing strains. The bactericidal activity of piperacillin was enhanced in combination with tazobactam. Tazobactam inhibited the penicillinases, and the oxyiminocephalosporinase produced by Proteus vulgaris, at low concentration. In these cases its activity was comparable with that of clavulanic acid and stronger than that of sulbactam. Tazobactam demonstrated a better inhibitory capability than sulbactam against the cephalosporinases tested. Tazobactam was able to inactivate intracellular beta-lactamase in Prot. vulgaris and Morganella morganii, confirming its ability to penetrate the cell membrane of these species.     

Comparative activity and spectrum of broad-spectrum beta-lactams (cefepime, ceftazidime, ceftriaxone, piperacillin/tazobactam) tested against 12,295 staphylococci and streptococci: report from the SENTRY antimicrobial surveillance program (North America: 2001-2002)

A contemporary collection of 12,295 North American isolates (2001-2002) consisting of Staphylococcus aureus (50%), coagulase-negative staphylococci (12%), Streptococcus pneumoniae (24%), beta-hemolytic streptococci (12%), and viridans-group streptococci (2%) were tested against broad-spectrum beta-lactams (cefepime, ceftazidime, ceftriaxone, imipenem, piperacillin/tazobactam) and comparator agents using a reference broth microdilution method to determine their continued effectiveness for empiric antimicrobial therapy. All isolates were very susceptible to vancomycin, linezolid and quinupristin/dalfopristin (>98%). Oxacillin-susceptible staphylococci were also highly susceptible to the tested beta-lactams (>98%) with the exception of ceftazidime (93%). beta-hemolytic streptococci were exquisitely susceptible (>99%) to penicillin and all other agents except for clindamycin (94%) and erythromycin (81%). Viridans group streptococci were routinely less susceptible than were other streptococci. S. pneumoniae remained susceptible to most agents (>91%) with the exceptions of erythromycin (74%) and penicillin (69%). Among beta-lactams tested against S. pneumoniae, ceftriaxone and cefepime continued to be very active against penicillin-susceptible (>99%) and intermediate (>98%) strains, but less active (80% and 82%, respectively) against penicillin-resistant isolates. These findings confirm that the newer cephalosporins (cefepime and ceftriaxone) among broad-spectrum beta-lactam agents have a spectrum of activity that remains comprehensive for the commonly isolated Gram-positive pathogens.     

In vitro activity of piperacillin, ticarcillin, mezlocillin, ticarcillin-clavulanic acid, aztreonam, ceftazidime, azlocillin, cefoperazone, and thienamycin against Pseudomonas aeruginosa

The in vitro susceptibility of 103 well-characterized strains of Pseudomonas aeruginosa to nine antimicrobial agents was assessed by means of the Kirby-Bauer disk diffusion assay and the microtiter minimal inhibitory concentration assay. The antimicrobials, from the most to the least active against P aeruginosa, were thienamycin greater than ceftazidime greater than piperacillin greater than azlocillin greater than cefoperazone greater than aztreonam greater than ticarcillin greater than ticarcillin-clavulanic acid greater than mezlocillin. The resistance patterns of the antimicrobial agents suggest that P aeruginosa resistant to a penicillin, cephalosporin, or aztreonam may be susceptible to thienamycin.     

Study on the relationship between pharmacokinetics and antibacterial activity: comparison between ceftriaxone and cefotaxime within the respiratory tract

The aim of this research was to collect precise data on the antibacterial activity of ceftriaxone and cefotaxime in the respiratory tract. The diffusion into pulmonary tissue and bronchial secretion and the antibacterial activity of the two antibiotics were evaluated in vivo by means of the inhibitory quotient. Ceftriaxone administered at a dosage of 1 g (i.m.) every 24 h resulted in antibacterial levels against the sensitive pathogens over a period of 24 h after each dose. The antibacterial protection afforded by cefotaxime, given at the dosage of 1 g (i.m.) every 12 h, was not as marked and did not extend over the interval between two administrations.     

Comparative pharmacokinetics of YM-13115, ceftriaxone, and ceftazidime in rats, dogs, and rhesus monkeys.

The pharmacokinetics of YM-13115, ceftriaxone, and ceftazidime were studied in rats, dogs, and rhesus monkeys (only YM-13115 and ceftriaxone were studied in rhesus monkeys). The plasma half-lives in rats were 48 min for YM-13115, 34 min for ceftriaxone, and 14 min for ceftazidime. In dogs, they were 21.9 min for YM-13115, 50.7 min for ceftriaxone, and 49.0 min for ceftazidime. In monkeys, they were 5.30 h for YM-13115 and 3.40 h for ceftriaxone. The 24-h urinary recoveries in rats were 26.7% of the dose for YM-13115, 32.0% for ceftriaxone, and 97.1% for ceftazidime. In dogs, they were 13.3% for YM-13115, 62.5% for ceftriaxone, and 86.3% for ceftazidime. In monkeys, they were 22.5% for YM-13115 and 29.3% for ceftriaxone. The 24-h biliary recoveries in rats were 72.2% for YM-13115, 61.8% for ceftriaxone, and 0.63% for ceftazidime.