Comparative pharmacokinetics and serum bactericidal activities of SCE-2787 and ceftazidime.

Ceftazidime and the new SCE-2787 are parenteral cephalosporins with a broad antimicrobial spectrum. Pharmacokinetics, serum bactericidal activities, and side effects were investigated in a randomized crossover study. A total of 12 healthy volunteers received a 20-min infusion of 1.5 g of SCE-2787 or 2.0 g of ceftazidime. Serum and urine concentrations were determined by the bioassay method and by high-pressure liquid chromatography (HPLC). The mean (+/- standard deviation) drug concentrations in serum at the end of infusion of SCE-2787 and ceftazidime were 124.4 +/- 23.8 and 233.1 +/- 54.1 mg/liter, respectively. The urine recovery of SCE-2787 was 87.8% +/- 5.5% of dose in 24 h and for ceftazidime was 85.8% +/- 6.3% of dose in 24 h. Metabolites of SCE-2787 could not be detected by HPLC in serum or urine. Pharmacokinetic parameters were calculated both with a noncompartmental analysis and on the basis of an open two-compartment model (drugs are administered into and eliminated from a central compartment only. However, reversible drug distribution from the central space occurs simultaneously into one peripheral space). The area under the concentration time curve from 0 h to infinity of SCE-2787 was 197.9 +/- 25.4 mg.h/liter, and that of ceftazidime was 334.2 +/- 40.0 mg.h/liter. SCE-2787 had a mean terminal half-life in the elimination phase of 109.0 +/- 15.3 min, while that of ceftazidime was 99.0 +/- 13.4 min. The volume of distribution at steady state of SCE-2787 was 17.1 +/- 1.6 liters/70 kg, and that of ceftazidime was 122.9 +/- 1.3 liters/70 kg. The mean residence time of SCE-2787 was 136.4 +/- 15.4 min, and that of ceftazidime was 122.9 +/- 12.7 min. The renal clearance per. 1.73 m2 of SCE-2787 was 103.1 +/- 12.3 ml/min, and that of ceftazidime was 80.6 +/- 13.2 ml/min. The serum bactericidal activities were measured with the microdilution method of Stratton and Reller (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977) against 40 clinically isolated strains. One hour after administration, we measured mean reciprocal bactericidal titers of SCE-2787 and ceftazidime, respectively, against Escherichia coli of 388 and 243, against Klebsiella pneumoniae of 395 and 138, against Pseudomonas aeruginosa of 13.0 and 12.7, and against Staphylococcus aureus of 32.2 and 4.0. No severe side effects were observed in this single drug administration.     

Comparative serum bactericidal activities of three doses of ciprofloxacin administered intravenously.

The pharmacokinetics and serum bactericidal activities of three intravenous doses of ciprofloxacin were studied comparatively in 30 patients. Single 200-, 300-, and 400-mg intravenous doses of ciprofloxacin were given over 30 min to 10 patients each, and serum samples were obtained at 0.5, 1, 2, 3, 4, 8, and 12 h after the start of the infusion. Serum drug concentrations were determined by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by using noncompartmental analysis methods. Serum bactericidal activity against clinical isolates of Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, Acinetobacter calcoaceticus, and Staphylococcus aureus was determined for samples obtained at 0.5, 4, 8, and 12 h. Excellent activity was demonstrated up to 12 h by all doses against E. coli and E. cloacae. Much poorer titers were observed for the remaining organisms, although the 400-mg dose prompted improved results against P. aeruginosa with a mean bactericidal titer of 1:2.9 at 8 h. In conclusion, while the 200-mg dose appears to be largely adequate for infections caused by members of the family Enterobacteriaceae, it seems that when P. aeruginosa is involved, 400 mg twice a day or even three times a day is more appropriate. Intravenous ciprofloxacin performs poorly against A. calcoaceticus and S. aureus, even at a higher dose.     

In vitro activities of cefotaxime, ceftriaxone, ceftazidime, cefpirome, and penicillin against Streptococcus pneumoniae isolates.

The in vitro activities of four extended-spectrum cephalosporins and benzyl penicillin were evaluated against 698 clinical isolates of Streptococcus pneumoniae, including 130 (19%) penicillin-intermediate and 84 (12%) penicillin-resistant strains. Cefotaxime and ceftriaxone were essentially identical in their antipneumococcal activities: both were active against penicillin-susceptible strains and most penicillin-intermediate strains. Cefpirome was twice as potent as cefotaxime and ceftriaxone against penicillin-resistant strains. Ceftazidime was 8- to 16-fold less active than cefotaxime and ceftriaxone against S. pneumoniae in vitro, and thus, its spectrum included only penicillin-susceptible strains.     

Comparative study of pharmacokinetics and serum bactericidal activity of ceftizoxime and cefotaxime.

Single 2-g intravenous doses of ceftizoxime (CZX) and cefotaxime (CTX) were given over 30 min to 10 adult volunteers in a crossover manner on two separate occasions. Concentrations of CZX, CTX, and the primary metabolite of CTX, desacetylcefotaxime (dCTX), in serum, suction-induced-blister fluid, and urine were determined by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by using an extended least-squares modeling program (MKMODEL). CZX exhibited a half-life in serum (2.05 h) longer than that of CTX (1.43 h) but comparable to that of dCTX (2.02 h). The percentage of penetration in blister fluid, estimated by area under the curve ratios, was significantly higher for CZX (164.4%) than for CTX (60.8%). Serum bactericidal activity, determined for volunteer samples at 1, 6, 8, and 12 h after patients were dosed, against clinical isolates of the Bacteroides fragilis group, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and Morganella morganii were significantly higher for CZX than those for CTX against members of the family Enterobacteriaceae at all times. Serum bactericidal titers against B. fragilis were also higher for CZX than for CTX at 1 h postinfusion. Neither CZX nor CTX exhibited any bactericidal activity at any other time against the B. fragilis group. In conclusion, the serum bactericidal activity of CZX was greater and more-prolonged than that of CTX against tested strains in spite of the in vitro synergistic contribution of dCTX to CTX, equal serum elimination half-lives of dCTX and CZX, and similar antibacterial activity and similar instability under microbiological testing for CZX and CTX.     

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.     

Susceptibilities of 177 penicillin-susceptible and -resistant pneumococci to FK 037, cefpirome, cefepime, ceftriaxone, cefotaxime, ceftazidime, imipenem, biapenem, meropenem, and vancomycin.

MICs of six extended-spectrum cephalosporins (cefotaxime, ceftriaxone, ceftazidime, FK 037, cefpirome, cefepime), three carbapenems (imipenem, meropenem, biapenem), and vancomycin for 49 penicillin-susceptible (S), 77 penicillin intermediate-resistant (I), and 51 penicillin-resistant (R) pneumococci were determined by agar dilution. Compared with ceftazidime (MICs for 90% of strains tested [MIC90s] of 2.0, 16.0, and 16.0 micrograms/ml for S, I, and R strains, respectively), all other cephalosporins yielded lower MICs (MIC90s of 0.06 to 0.125, 0.5 to 1.0, and 1.0 to 2.0 micrograms/ml against S, I, and R strains, respectively). All three carbapenems were very active, with MIC90s, even for R strains, of < or = 1.0 micrograms/ml. All strains were susceptible to vancomycin (MIC90 of 0.5 micrograms/ml).     

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.     

Pharmacokinetic disposition and bactericidal activities of cefepime, ceftazidime, and cefoperazone in serum and blister fluid.

Cefepime is a new broad-spectrum cephalosporin with excellent gram-positive and gram-negative activity including activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacter cloacae. The pharmacokinetic disposition of cefepime is similar to that of ceftazidime. We compared the pharmacokinetic characteristics and the extent and duration of bactericidal activity in serum and suction-induced blister fluid after single 2-g intravenous doses of cefepime, ceftazidime, and cefoperazone given to healthy subjects. One clinical isolate each of E. cloacae, P. aeruginosa, and S. aureus was used to assess bactericidal activity. Results of the pharmacokinetic analysis were similar to previously reported data for these drugs. The high serum protein binding of cefoperazone (approximately 90%) contributed to poor blister fluid penetration. The other drugs penetrated well into this fluid compartment. Cefepime showed significantly greater bactericidal activity in serum and blister fluid against E. cloacae than the other study drugs, ceftazidime was significantly better in serum and blister fluid against P. aeruginosa, and cefoperazone was significantly better against S. aureus only in serum. None of the study drugs had significant bactericidal activity in blister fluid against S. aureus. Cefepime is a promising antimicrobial agent for the treatment of infections due to E. cloacae.     

Levofloxacin pharmacokinetics and serum bactericidal activities against five enterobacterial species

After oral administration of 500 mg of levofloxacin to 12 volunteers, we investigated the pharmacokinetics and serum bactericidal activities (SBAs) against five strains of members of the family Enterobacteriaceae. Pharmacokinetic data were as follows: maximum concentration in serum, 6.36 +/- 0.57 mg/liter; area under the concentration-time curve, 43.6 +/- 6.23 mg. h/liter; elimination half-life 4.23 +/- 0.87 h. SBAs were present for 24 h against Escherichia coli and Citrobacter freundii. The SBAs at 1, 12, and 24 h after administration against E. coli were 1:108, 1:29, and 1:7, respectively, and those against Citrobacter freundii were 1:74, 1:25, and 1:7, respectively. The SBAs were present for 12 h against the other three organisms tested. The SBAs against Serratia marcescens were 1:28 and 1:9 at 1 and 12 h, respectively; the SBAs against Klebsiella pneumoniae were 1:25 and 1:7 at 1 and 12 h, respectively; and the SBAs against Enterobacter cloacae were 1:24 and 1:10 at 1 and 12 h, respectively.     

Effect of protein binding on serum bactericidal activities of ceftazidime and cefoperazone in healthy volunteers.

The effect of protein binding on antibiotic efficacy is controversial. The pharmacologic effect of an antibiotic is believed to be related to its unbound concentration at the site of infection. It is unknown whether antibiotics with a low degree of serum protein binding are clinically superior to antibiotics that are highly protein bound. In a randomized, crossover investigation, the serum bactericidal activities of a single dose of ceftazidime (30 mg/kg) and cefoperazone (30 mg/kg) were studied in six healthy volunteers against three clinical isolates of Pseudomonas aeruginosa for which both antibiotics had similar MICs and MBCs. Serum samples were collected over 12 h. The total and unbound antibiotic concentrations were determined by high-pressure liquid chromatography. Mean peak total concentrations of ceftazidime and cefoperazone in serum were 101.7 +/- 18.6 and 264.1 +/- 149.6 micrograms/ml, respectively. Due to its lower protein binding (21 +/- 6%), ceftazidime had significantly higher unbound concentrations in serum than did the highly bound cefoperazone (91.5 +/- 2%). Mean peak unbound concentrations were 78.5 +/- 12.5 and 24.2 +/- 17.8 micrograms/ml for ceftazidime and cefoperazone, respectively. The unbound concentration of ceftazidime at each sampling time was higher than that of cefoperazone. Although total concentrations were consistently higher than the MICs, serum containing cefoperazone showed minimal bactericidal activity against the isolates. In contrast, despite lower total concentrations, ceftazidime had greater antibacterial activity than cefoperazone. Serum bactericidal activity was more closely related to unbound rather than total antibiotic concentrations. Our data support the concept that only the unbound drug is microbiologically active.     

Comparative pharmacokinetics of ceftazidime and moxalactam

The pharmacokinetics of ceftazidime and moxalactam were compared after intravenous and intramuscular administration of single 1-g doses to eight healthy volunteers in a crossover study. The bioavailability of the antibiotics after administration by either route was almost complete. Both drugs had similar areas under the serum curves. Significant differences between ceftazidime and moxalactam were observed with respect to the apparent volume of distribution (18.4 and 24.1 liters, respectively), to the terminal half-life (1.6 versus 2.0 h), and to urinary recovery of the active compound (96 versus 79%). Ceftazidime was almost completely eliminated by renal excretion (greater than 96%), whereas about 20% of the moxalactam was eliminated by nonrenal mechanisms. The concentrations of ceftazidime and moxalactam in serum after a 1-g dose exceeded the concentrations required to inhibit 90% of the Enterobacteriaceae for about 8 and 10 h, respectively. The levels of ceftazidime and moxalactam in serum exceeded the 90% minimal inhibitory concentration of Pseudomonas aeruginosa for about 6 and 1 h, respectively.     

Comparative multiple-dose pharmacokinetics of cefotaxime, moxalactam, and ceftazidime

The pharmacokinetics of cefotaxime, moxalactam, and ceftazidime were investigated in six human volunteers who received in a crossover fashion doses of 0.5, 1.0, and 2.0 g of each drug by a 5-min infusion. Doses of 1.0 g were repeated after the administration of probenecid. Serum and urine concentrations were assayed with an agar diffusion method. Serum concentrations of moxalactam exceeded those of ceftazidime at all times and were distinctly higher than those of cefotaxime. The normalized area under the concentration time curve (defined as the ratio of the area under the curve per dose) reflects this relationship: compared with cefotaxime the normalized area under the curve of moxalactam was 3 to 4 times higher, and that of ceftazidime was 2 to 3 times higher. By intra-individual comparisons, the area under the curve of moxalactam was 44% larger than that of ceftazidime. With increasing doses, cefotaxime exhibited a nonlinear increase of the area under the curve. The half-lives of moxalactam, ceftazidime, and cefotaxime were 2.34, 1.95, and 1.16 h, respectively. The volume of distribution averaged 0.20 ± 0.03, 0.23 ± 0.02, and 0.25 ± 0.04 liters per kg, and the mean total body clearance was 84, 131, and 328 ml/min for moxalactam, ceftazidime, and cefotaxime, respectively. The 24-h urinary recovery was highest for moxalactam (75 ± 4%) followed by ceftazidime (68 ± 11%) and cefotaxime (53 ± 6%). The influence of probenecid on serum concentrations, half-life, area under the curve, and clearance was most apparent with cefotaxime, whereas the pharmacokinetics of moxalactam and ceftazidime were only slightly affected. After the 0.5− and 2.0− g doses of cefotaxime, desacetyl-cefotaxime activity (determined by high-pressure liquid chromatography) reached a peak of 2.7 and 9.9 μg/ml and declined with a half-life of 1.9 and 1.4 h. The ratio of the R(−) and S(−) epimers of moxalactam, which could be differentiated by high-pressure liquid chromatography, fell rapidly from 0.81 at 0.17 h to 0.5 at 5 h, indicating the presence of twice as much of the microbiologically less active S(−) epimer. From a pharmacokinetic standpoint it appears reasonable to conclude that moxalactam and possibly ceftazidime could be administered twice daily and that cefotaxime could be administered three or even four times daily.     

Comparative serum bactericidal activity against test anaerobes in volunteers receiving imipenem, clindamycin, latamoxef and metronidazole

Ten healthy volunteers received on separate days the following regimens: imipenem 500 mg, clindamycin 600 mg, latamoxef 1 g, and metronidazole 500 mg. The antibiotics were given intravenously as an infusion over 15 min. Blood samples were obtained before and 30 min, 1 and 6 h after the start of the infusion. Serum bacteriostatic and bactericidal activities were measured against the following strains of strict anaerobes: two strains of Bacteroides fragilis, one strain each of B. vulgatus, B. thetaiotaomicron, B. oralis, Fusobacterium symbiosum, Eubacterium lentum, Clostridium perfringens, and Peptostreptococcus magnus. Sera from patients receiving clindamycin showed the highest inhibitory and bactericidal activities except against B. thetaiotaomicron and F. symbiosum. Imipenem had similar inhibitory and bactericidal activity to that shown by latamoxef. Metronidazole had a moderate activity against all strains although the activity persisted for 6 h. Latamoxef was the most active antibiotic against the test strain of C. perfringens.     

In vitro bactericidal activities of gentamicin, cefazolin, and imipenem in peritoneal dialysis fluids.

Continuous ambulatory peritoneal dialysis is an important modality of therapy for patients with renal disease. However, peritonitis continues to be a major risk factor and is usually treated by intraperitoneal administration of antimicrobial agents. Few data are available concerning the stability of antimicrobial agents in peritoneal dialysis solution beyond 48 h. Our investigation was designed to establish the chemical and biological stability of gentamicin alone and in combination with cefazolin in peritoneal dialysis solution at 6 and 72 h by an immunoassay and by an in vitro bactericidal test against American Type Culture Collection (Rockville, Md.) strains of Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis. In addition, uninfected peritoneal dialysis effluent was inoculated with three American Type Culture Collection strains and gentamicin or imipenem. Gentamicin alone or in combination with cefazolin was not altered chemically and was bactericidal for Staphylococcus spp. but not P. aeruginosa. In contrast, imipenem was active against both Staphylococcus spp. and P. aeruginosa. Undefined factors other than inactivation of gentamicin may be responsible for the lack of bactericidal activity and treatment failure of Pseudomonas infections.     

Crossover assessment of serum bactericidal activity and pharmacokinetics of ciprofloxacin alone and in combination in healthy elderly volunteers.

To better define the pharmacokinetics and serum bactericidal activity (SBA) of ciprofloxacin and other antimicrobial agents in the elderly, six healthy (greater than 65 years) volunteers with normal renal function were given ciprofloxacin alone orally, ciprofloxacin plus rifampin orally, ciprofloxacin plus clindamycin orally, rifampin alone orally (three volunteers), and, for comparison of SBA against gram-positive cocci, vancomycin intravenously. Mean peak ciprofloxacin concentrations and other pharmacokinetic parameters were not altered significantly by coadministration of either rifampin or clindamycin. Ciprofloxacin had somewhat greater SBA against the oxacillin-susceptible and oxacillin-resistant Staphylococcus aureus strains tested than did vancomycin, but rifampin was by far the most active single agent tested. The SBA of rifampin against S. aureus was modestly antagonized during combination therapy with ciprofloxacin, but substantial SBA still was present. The ciprofloxacin SBA against S. aureus was completely antagonized by clindamycin if the strains were susceptible to the latter agent. Ciprofloxacin had modest SBA against group A streptococci and no SBA against the three pneumococcal strains tested. All of the regimens had poor to absent SBA against Enterococcus faecalis. By contrast, ciprofloxacin had excellent SBA against Escherchia coli and Klebsiella pneumoniae and moderate SBA against Pseudomonas aeruginosa. Combination therapy with rifampin or clindamycin in general enhanced the SBA against the nonenterococcal streptococci and had no effect on the SBA against the gram-negative bacilli.     

Comparative antimycobacterial activities of ofloxacin, ciprofloxacin and grepafloxacin.

Infections caused by non-tuberculous mycobacteria and multidrug-resistant Mycobacterium tuberculosis are difficult to treat. New compounds potentially active against these bacteria are therefore constantly being sought. Among them is grepafloxacin, a new C5 fluoroquinolone. A panel of 130 isolates of mycobacteria including 33 M. tuberculosis isolates and 97 isolates of different species of atypical mycobacteria were analysed for susceptibility to grepafloxacin, ofloxacin and ciprofloxacin. The MICs of these fluoroquinolones were determined using the agar-dilution method. Different mycobacterial species showed different degrees of susceptibility to grepafloxacin, ofloxacin and ciprofloxacin but little difference was observed between the MICs of the three antibiotics against strains of the same mycobacterial species. In addition, to evaluate the intracellular activity of these drugs, six strains of mycobacteria were studied using a human-macrophage infection model. Preliminary results of macrophage experiments showed that grepafloxacin was more active than ofloxacin and ciprofloxacin, particularly against Mycobacterium kansasii and, to a lesser degree, against Mycobacterium avium complex and Mycobacterium marinum. However, the three fluoroquinolones had comparable activities against M. tuberculosis.     

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.     

Comparative activities of ciprofloxacin and ceftazidime against Klebsiella pneumoniae in vitro and in experimental pneumonia in leukopenic rats.

The antibacterial activities of ciprofloxacin and ceftazidime against Klebsiella pneumoniae in vitro and in vivo were compared. Although there was only a minor difference between the MBCs of both drugs, the bacterial killing rate of ciprofloxacin in vitro was very fast in comparison with that of ceftazidime. Similarly, the intravenous administration of ciprofloxacin at 1 h after bacterial inoculation resulted in effective bacterial killing in the lungs of leukopenic rats. This killing was dose dependent, in contrast to the dose-independent bactericidal effect of ceftazidime. The high antibacterial activity of ciprofloxacin in the lungs as compared with that of ceftazidime was also reflected in its therapeutic efficacy in K. pneumoniae pneumonia and septicemia in leukopenic rats when these infections were treated at 6-h intervals over 4 days, starting at 5 h after bacterial inoculation. Concentrations of ciprofloxacin and ceftazidime in lung tissue were not significantly different. Regarding the antibacterial activity of both drugs against K. pneumoniae in relation to the bacterial growth rate in vitro and in the lungs of leukopenic rats, ciprofloxacin killed K. pneumoniae organisms that were not actively growing, whereas ceftazidime did not. In addition, it was demonstrated that when the intravenous administration of antibiotic was delayed from 1 h up to 24 h after bacterial inoculation, ceftazidime lost its antibacterial activity in the lungs and blood of leukopenic rats, whereas ciprofloxacin was still very effective. These data suggest that the capacity of an antibiotic to kill bacteria at a slow growth rate may be relevant for its therapeutic effect in established infections, in which slowly growing bacteria form a substantial part of the total bacterial population.     

Comparative pharmacokinetics and serum bactericidal activity of mezlocillin, ticarcillin and piperacillin, with and without gentamicin

We compared the serum levels, pharmacokinetics and serum bactericidal activity after intravenous infusions of 5 g of each of three anti-pseudomonal penicillins--ticarcillin, mezlocillin and piperacillin alone and in combination with 80 mg gentamicin in normal volunteers. Gentamicin levels were significantly lower when administered with ticarcillin than when administered with mezlocillin or piperacillin. Serum levels of ticarcillin and piperacillin immediately after the infusion were similar (approximately 450 mg/l) and were higher than mezlocillin at 350 mg/l, but by 6 h, levels of all three penicillins were less than 10 mg/l. Overall, the geometric mean bactericidal titres produced in the serum against organisms which commonly infect cancer patients with granulocytopenia were highest with the piperacillin-gentamicin combination. However, except for the mezlocillin-gentamicin combination against Pseudomonas aeruginosa, serum bactericidal titres of all three penicillin-gentamicin regimes were greater than 1:8 at zero and 2 h after the infusion against the organisms tested. It is unlikely that these differences in the three penicillin-gentamicin combinations will be apparent in the outcome of clinical trials for empiric therapy of fever in the cancer patient with granulocytopenia.