Efficacies of imipenem, meropenem, cefepime, and ceftazidime in rats with experimental pneumonia due to a carbapenem-hydrolyzing beta-lactamase-producing strain of Enterobacter cloacae.

The antibacterial activities of imipenem-cilastatin, meropenem-cilastatin, cefepime and ceftazidime against Enterobacter cloacae NOR-1, which produces the carbapenem-hydrolyzing beta-lactamase NmcA and a cephalosporinase, and against one of its in vitro-obtained ceftazidime-resistant mutant were compared by using an experimental model of pneumonia with immunocompetent rats. The MICs of the beta-lactams with an inoculum of 5 log(10) CFU/ml were as follows for E. cloacae NOR-1 and its ceftazidime-resistant mutant, respectively: imipenem, 16 and 128 microg/ml, meropenem, 4 and 32 microg/ml, cefepime, <0.03 and 1 microg/ml, and ceftazidime, 1 and 512 microg/ml. The chromosomally located cephalosporinase and carbapenem-hydrolyzing beta-lactamase NmcA were inducible by cefoxitin and meropenem in E. cloacae NOR-1, and both were stably overproduced in the ceftazidime-resistant mutant. Renal impairment was induced (uranyl nitrate, 1 mg/kg of body weight) in rats to simulate the human pharmacokinetic parameters for the beta-lactams studied. Animals were intratracheally inoculated with 8.5 log(10) CFU of E. cloacae, and therapy was initiated 3 h later. At that time, animal lungs showed bilateral pneumonia containing more than 6 log(10) CFU of E. cloacae per g of tissue. Despite the relative low MIC of meropenem for E. cloacae NOR-1, the carbapenem-treated rats had no decrease in bacterial counts in their lungs 60 h after therapy onset compared to the counts for the controls, regardless of whether E. cloacae NOR-1 or its ceftazidime-resistant mutant was inoculated. A significant decrease in bacterial titers was observed for the ceftazidime-treated rats infected with E. cloacae NOR-1 only. Cefepime was the only beta-lactam tested effective as treatment against infections due to E. cloacae NOR-1 or its ceftazidime-resistant mutant.

Treatment of experimental pneumonia in rats caused by a PER-1 extended-spectrum beta-lactamase-producing strain of Pseudomonas aeruginosa.

The antibacterial activity of imipenem, cefepime and piperacillin-tazobactam alone or in combination with amikacin against a Pseudomonas aeruginosa strain producing an extended-spectrum beta-lactamase (PER-1) were compared using an experimental model of pneumonia in non-leucopenic rats. Animals were infected intratracheally with 8.0 +/- 0.4 log10 cfu of P. aeruginosa, and therapy was initiated 3 h later, by which time animal lungs showed bilateral pneumonia containing >7 log10 P. aeruginosa cfu/g of tissue. Since rats eliminate antibiotics much more rapidly than humans, renal impairment was induced in all animals to simulate the pharmacokinetic parameters of humans. MICs determined using an inoculum of 4 log10 cfu/mL were as follows: imipenem, 1 mg/L; cefepime, 8 mg/L; piperacillin-tazobactam, 32 mg/L; and amikacin, 16 mg/L. A noticeable inoculum effect was observed with the four antimicrobial agents tested, which was greatest for cefepime and piperacillin-tazobactam. In-vitro studies indicated that imipenem was the beta-lactam with the greatest bactericidal effect and that amikacin was synergic only in combination with cefepime and imipenem. Cefepime and piperacillin-tazobactam alone failed to decrease bacterial counts in the rats' lungs 60 h after therapy onset, whereas imipenem and, to a lesser extent, amikacin significantly reduced the number of viable microorganisms. Combination of amikacin with any of the three beta-lactams tested was synergic, despite a high amikacin MIC for the infecting strain. These results paralleled our in-vitro data showing a marked inoculum effect for cefepime and piperacillin-tazobactam. Based on the results of this study, the best treatment for infections caused by this type of extended-spectrum beta-lactamase-possessing strain would be imipenem plus amikacin.

Pharmacokinetics of cefpirome during the posttraumatic systemic inflammatory response syndrome.

OBJECTIVE: To determine the pharmacokinetic parameters of cefpirome, a new so-called fourth-generation cephalosporin, in previously healthy trauma patients with posttraumatic systemic inflammatory response syndrome (SIRS) and to compare them to parameters obtained in matched, healthy volunteers. DESIGN: A prospective study. SETTING: 12-bed surgical intensive care unit in a university hospital. PATIENTS: 9 severe [Injury Severity Score, median (range) 29 (16-50)] trauma patients on mechanical ventilation with proven or suspected cefpirome-susceptible nosocomial infection, with no renal or hepatic failure, and healthy volunteers matched for age (+/- 5 years), sex, and body surface area (+/- 10%) were enrolled. All were men. INTERVENTIONS: Cefpirome (2 g twice daily) was continuously infused over a 0.5 h period alone or concomitantly with ciprofloxacin (400 mg over 1 h, twice daily). MEASUREMENTS AND MAIN RESULTS: Antibiotic concentrations in plasma were measured by high-performance liquid chromatography; their pharmacokinetic parameters were evaluated at 12 time points after the first drug administration using a noncompartmental model. Cefpirome pharmacokinetic parameters for the two groups were similar despite a wider variation for trauma patients. Specifically, the median (range) time during which the cefpirome concentration in plasma remained over 4 mg/l (corresponding to the French lower cutoff determining cefpirome susceptibility) was 9.5 (7- > 12) and 9 (8-12) h for trauma patients and healthy volunteers, respectively. In the group of five patients receiving combined antibiotic therapy, the interindividual variability of pharmacokinetics was wider for ciprofloxacin than for cefpirome. CONCLUSION: No major pharmacokinetic modification was noted when cefpirome was given to trauma patients with posttraumatic SIRS without significant organ failure, indicating that no dosage adjustment seems required in this population. However, larger studies including determination of antibiotic levels in tissues are warranted to confirm these results.

Efficacies of cefepime, ceftazidime, and imipenem alone or in combination with amikacin in rats with experimental pneumonia due to ceftazidime-susceptible or -resistant Enterobacter cloacae strains.

The antibacterial activities of human regimens of cefepime, ceftazidime, and imipenem alone or in combination with amikacin against an isogenic pair of Enterobacter cloacae strains (wild type and its corresponding derepressed cephalosporinase mutant) were compared by using our nonlethal model of pneumonia with 180 immunocompetent rats. Compared with untreated animals, all beta-lactam-treated rats, except those inoculated with the mutant isolate and receiving ceftazidime, had significantly lower bacterial counts in their lungs 60 h after the onset of therapy. Although the combination of a beta-lactam and amikacin was more bactericidal than each corresponding antimicrobial agent alone, true synergy was noted only with cefepime and imipenem against the constitutive derepressed strain.

Pharmacokinetics and absolute bioavailability of ciprofloxacin administered through a nasogastric tube with continuous enteral feeding to critically ill patients.

OBJECTIVE: To determine the pharmacokinetics and absolute bioavailability of ciprofloxacin in 12 critically ill patients receiving continuous enteral feeding. DESIGN: a prospective, cross-over study. SETTING: 12-bed surgical intensive care unit in a University Hospital. PATIENTS: 12 stable critically ill patients on mechanical ventilation and receiving continuous enteral feeding (Normoreal fibres) without diarrhea or excessive residual gastric contents ( < 200 ml/4 h). None had gastro-intestinal disease, renal insufficiency (estimated creatinine clearance > or = 50 ml/min) or was receiving medications that could interfere with ciprofloxacin absorption or metabolism. MEASUREMENTS AND MAIN RESULTS: The study was carried out after the fourth (steady state) b. i. d. intravenous (i. v.) 1-h infusion of 400 mg and the second b. i. d. nasogastric (NG) dose of 750 mg (crushed tablet in suspension). Plasma concentrations were measured by high-performance liquid chromatography. The median (range) peak concentration after i. v. infusion was 4.1 (1.5-7.4) mg/l, and that after NG administration was 2.3 (0.7-5.8) mg/l, occurring 1.25 (0.75-3.33) h after dosing. The median [range] areas under plasma concentration-time curves were similar for the two administration routes (10.3 [3.3-34.6] and 8.4 [3.6-53.4] for i.v. infusion and NG administration, respectively). Ciprofloxacin bioavailability ranges from 31 to 82 % (median, 44%). CONCLUSIONS: In tube-fed critically ill patients, a switch to the NG ciprofloxacin after initial i. v. therapy to simplify the treatment of severe infections is restricted to those for whom serial assessments of ciprofloxacin levels are routinely available.

Cefepime and amikacin synergy in vitro and in vivo against a ceftazidime-resistant strain of Enterobacter cloacae.

The activities of cefepime and amikacin alone or in combination against an isogenic pair of Enterobacter cloacae strains (wild type and stably derepressed, ceftazidime-resistant mutant) were compared using an experimental model of pneumonia in non-leucopenic rats. Animals were infected by administering 8.4 log10 cfu of E. cloacae intratracheally, and therapy was initiated 12 h later. At that time, the animals' lungs showed bilateral pneumonia and contained more than 7 log10 E. cloacae cfu/g tissue. Because rats eliminate amikacin and cefepime much more rapidly than humans, renal impairment was induced in all animals to simulate the pharmacokinetic parameters of humans. In-vitro susceptibilities showed an inoculum effect with cefepime proportional to the bacterial titre against the two strains, but more pronounced with the stably derepressed mutant strain, whereas with bacterial concentrations of up to 7 log10 cfu/mL, no inoculum effect was observed with amikacin. In-vitro killing indicated that antibiotic combinations were synergic only at intermediate concentrations. At peak concentrations, the combination was merely as effective as amikacin alone. At trough concentrations, a non-significant trend towards the superiority of the combination over each antibiotic alone was noted. Moreover, cefepime was either bacteriostatic or permitted regrowth of the organisms in the range of antibiotic concentrations tested. Although each antibiotic alone failed to decrease bacterial counts in the lungs, regardless of the susceptibility of the strain used, the combination of both antibiotics was synergic and induced a significant decrease in the lung bacterial count 24 h after starting therapy when compared with tissue bacterial numbers in untreated animals or animals treated with either antibiotic alone. No resistant clones emerged during treatment with any of the antibiotic regimens studied.

Cefepime and amikacin synergy against a cefotaxime-susceptible strain of Enterobacter cloacae in vitro and in vivo.

We developed an experimental model of pneumonia to evaluate the efficacy of new antibiotic regimens against Enterobacter cloacae. Rats were infected by administering 8.5 log10 cfu E. cloacae intratracheally, and therapy was initiated 24 h later. At that time, animals' lungs showed bilateral pneumonia containing more than 7 log10 cfu/g of tissue. Because rats eliminate amikacin and cefepime much more rapidly than humans, renal impairment was induced in all animals to simulate the pharmacokinetic parameters in humans. Using this model, we compared the bactericidal activities of cefepime and amikacin alone or in combination against the same cefotaxime-susceptible E. cloacae strain. The MICs of cefepime and amikacin for this strain were 0.5 and 2 mg/L, respectively. In-vitro killing studies showed that antibiotic combinations were synergic only at intermediate concentrations. At peak concentrations, the combination was only as effective as amikacin alone. At trough concentrations, a non-significant trend towards the superiority of the combination over cefepime alone was found. In-vivo studies showed that each antibiotic alone failed to decrease bacterial counts in the lungs except at 6 h, whereas the combination of both antibiotics induced a significant decrease in the lung bacterial count 6, 12 and 24 h after the onset of therapy when compared with tissue bacterial numbers in untreated animals or animals treated with either antibiotic alone. In-vivo synergy between cefepime and amikacin was observed at the three time points studied. No resistant clones emerged during treatment with any of the antibiotic regimens studied.

Monitoring of 8-methoxypsoralen during extracorporeal photochemotherapy: evidence for a "first-dose" effect.

Therapeutic monitoring of 8-methoxypsoralen (8-MOP) was studied in 12 patients (age range 43-85 years, weight range 48-76 kg) treated for Sezary's syndrome by extracorporeal photochemotherapy (ECP) for 14-41 months. Before the beginning of each ECP cycle (2 sessions on consecutive days at about 4-week intervals), a blood sample was drawn to determine the 8-MOP plasma concentration 2 h after drug ingestion. Plasma 8-MOP levels were measured using a high-performance liquid chromatography method with spectrophotometric detection. Monitoring parameters (dose, 2-h plasma 8-MOP concentration) showed important interindividual and intraindividual variations. The 8-MOP dose ranged from 0.57 to 1.04 mg/kg. Intraindividual variations of 2-h 8-MOP levels ranged from 21% to 75%. Of the 652 measurements, 13% were < 100 ng/ml, the therapeutic threshold for effective ECP; in three of the seven patients, increasing the dose obtained levels exceeding the therapeutic threshold, i.e, the absorption was not saturable. Orthogonal regression analysis between plasma 8-MOP concentrations measured in two consecutive ECP sessions showed a first-dose effect: the 2-h plasma 8-MOP concentration was significantly lower after the first administration than after the second (approximately 1.26-fold). Because 8-MOP has been proven to be a potent suicide inhibitor of drug metabolism in rats and humans, it is possible that 8-MOP had an inhibitory effect on its own metabolism within the therapeutic dose range for ECP, which would explain in part the inter- and intraindividual variability in 8-MOP kinetics and first-dose effect.

Pharmacokinetic interaction between cefdinir and two angiotensin-converting enzyme inhibitors in rats.

The pharmacokinetic interaction between cefdinir and an angiotensin-converting enzyme inhibitor (captopril or quinapril) was investigated in rats. The linearity of cefdinir pharmacokinetics was demonstrated in three groups of rats receiving 10, 20, or 40 mg of cefdinir per kg of body weight intravenously. Then, three other groups of rats were established as follows: group 1 (n = 5) received cefdinir (10 mg/kg) intravenously, and 12 blood samples per rat were drawn between 0 and 8 h after injection of the dose; group 2 (n = 5) was treated in the same way as group 1, but captopril (0.8 mg/kg) was coadministered by intraintestinal injection into all animals; group 3 (n = 6) was treated in the same way as group 2, but quinapril (0.8 mg/kg) replaced captopril. Plasma cefdinir concentrations were measured by liquid chromatography, and the data were analyzed by a noncompartmental method. Finally, three groups of four or five rats each were set up as described above, but the cefdinir dose was 20 mg/kg and the animals were sacrificed 1 h after drug injection to collect blood to determine the unbound cefdinir fraction (fu) by ultrafiltration. The angiotensin-converting enzyme inhibitors increased the mean cefdinir area under the concentration-time curve up to 8 h by a factor of 1.8 (captopril; P < 0.05) and a factor of 3.5 (quinapril; P < 0.05). With captopril, mean cefdinir clearance was decreased by a factor of 2, and the volume of distribution increased by the same factor, while the fu increased from 15.4% +/- 3.0% (cefdinir alone) to 22.8% +/- 10.9% (cefdinir plus captopril). Captopril increased the cefdinir half-life from 0.62 +/- 0.17 to 2.92 +/- 0.95 h. With quinapril, the interaction was so strong that no elimination phase was detectable in four of the six rats, and therefore, no pharmacokinetic parameter values other than the cefdinir fu could be calculated; the cefdinir fu increased to 25.1% +/- 11.1%. It is concluded that captopril and quinapril (and/or their metabolites) have a major impact on the disposition of cefdinir in rats, probably by competition at the plasma protein-binding level and at the tubular anionic carrier level. This latter mechanism should also be relevant in humans.

Influence of experimental rat model of multiple organ dysfunction on cefepime and amikacin pharmacokinetics.

We adapted an experimental model of multiple organ dysfunction to study the alterations it induces in the pharmacology of cefepime and amikacin. The half-lives of both antibiotics were significantly prolonged because of nonsignificant enhancement of the volume of distribution and reduced renal elimination. In the presence of multiple organ dysfunction, the concentration of each antibiotic in the lungs, compared with that in the lungs of healthy controls, was significantly decreased, despite similar concentrations in plasma, indicating that the application of a standard antibiotic concentration in plasma could lead to underdosage in tissues during the initial days of therapy.

Assessment of two penicillins plus beta-lactamase inhibitors versus cefotaxime in treatment of murine Klebsiella pneumoniae infections.

The in vivo efficacies of piperacillin, piperacillin plus tazobactam, ticarcillin, ticarcillin plus clavulanic acid, piperacillin plus clavulanic acid, and cefotaxime were compared in a mouse model of pneumonia induced by the SHV-1 beta-lactamase-producer Klebsiella pneumoniae. Each antibiotic was injected either once intraperitoneally at 24 h postinfection or at repeated times during 24 h. The efficacies of the drugs and therapeutic protocols were assessed by counting viable bacteria recovered from the lungs of mice sacrificed at selected times. No emergence of beta-lactam-resistant organisms was detected. Ticarcillin at 300 mg/kg was ineffective. Repeated injections of piperacillin at 300 mg/kg, either alone or in combination with tazobactam (8:1), led to a significant decrease in bacterial counts, but this was followed by bacterial regrowth. The pharmacokinetic analysis demonstrated that this short-lasting antibacterial effect was not due to a failure of piperacillin and/or tazobactam to penetrate the lungs. The combinations of ticarcillin at 300 mg/kg plus clavulanic acid (15:1) and piperacillin at 300 mg/kg plus tazobactam (4:1) were proven to be effective in that they decreased the bacterial burden in the lungs from 10(5) to < 10(3) CFU. This dose effect of tazobactam can be explained by its dose-dependent penetration in the lungs. Cefotaxime at 100 mg/kg and the combination of piperacillin (slightly hydrolyzed by SHV-1) at 300 mg/kg plus clavulanic acid (15:1) led to the best efficacy. Both of these treatments induced a decrease in bacterial counts of nearly 4 log10 units. The survival rates correlated with the quantitative measurements of in vivo bacterial killing. These experimental results obtained from the restricted animal model used here may help in the design of further protocols for clinical trials.

Comparative trial of Hexabrix (320 mg iodine/ml), iohexol (300 mg iodine/ml) and iopamiron (300 mg iodine/ml) in cerebral and spinal angiography: a preliminary report.

A comparison has been carried out of results of cerebral and spinal-cord angiography with two non-ionic contrast media, iohexol and Iopamiron, and a low-osmolality contrast medium, Hexabrix. A comparative study of iohexol, Hexabrix, and Iopamiron was carried out in a first group of 41 patients, and Hexabrix was compared with Iopamiron in a second group of 56. Evaluation criteria included local and general safety, as well as quality of angioscopy and angiography. In the first group of patients there were no significant differences in safety between the three agents. On the other hand, quality of visualisation during angioscopy with Hexabrix was clearly better. In the second group, safety and quality of the radiographic images were identical; however, once again, quality of angioscopy was better with Hexabrix than with Iopamiron. We conclude that Hexabrix appears to be the best opacifying agent currently available for cerebral and spinal-cord angiography. While results with Iopamiron were quite similar, the latter agent is slightly more expensive.

Influence of venous return on baroreflex control of heart rate during lumbar epidural anesthesia in humans.

The role of variation of venous return on baroreflex control of heart rate during lumbar epidural anesthesia was investigated in 12 unpremedicated patients. Group 1 patients (n = 6) received 8 ml of 0.5% plain bupivacaine in the epidural space (L3-4) (mean upper level of analgesia at T10). Group 2 patients (n = 6) received 8 ml of saline at the same level in the epidural space. Following the epidural injection, phenylephrine (PHE) and nitroglycerin (NTG) were employed to alter the stimulation of baroreceptor sites before and during application of lower body positive pressure (LBPP). Plasma bupivacaine, catecholamines, renin activity, and vasopressin were assayed. In contrast to saline, epidural bupivacaine induced a decrease in systolic arterial and right atrial pressures (-11 +/- 4 and -3.2 +/- 0.7 mmHg, respectively, mean +/- SEM) without change in heart rate, an increase in baroreflex slopes during PHE and NTG injections (+5.9 +/- 1.6 ms/mmHg and +2.8 +/- 0.9 ms/mmHg, respectively), and a decrease in plasma norepinephrine (-248 +/- 89 pg/ml). The application of LBPP restored hemodynamic and reflex variables to preepidural analgesia values, whereas plasma catecholamines decreased further. Plasma renin activity and vasopressin were not modified at any time in either groups. This study indicates that lumbar epidural anesthesia enhances cardiac vagal tone mainly through a decrease in venous return.

Attenuation by diltiazem of arterial baroreflex sensitivity in man.

The effect of oral diltiazem 120 mg, on the responses to baroreflex activation and deactivation by phenylephrine and nitroglycerin, respectively, were investigated in normotensive subjects, with simultaneous measurement of plasma catecholamine levels. Diltiazem significantly reduced the tachycardia induced by bolus injections of nitroglycerin and abolished the concomitant increase in plasma noradrenaline. It also significantly decreased the bradycardiac response to phenylephrine infusion. Diltiazem reduced, although not significantly so, the bradycardia induced by boluses of phenylephrine. The overall reduction in baroreflex sensitivity, which might contribute to the limited tachycardiac effect of diltiazem in man, is consistent with the drug-induced attenuation of the sympathetic and also of the parasympathetic components of the baroreceptor reflex.