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O Petitjean

Publications and source records attributed to O Petitjean.

At least 19 recordsLinked to original sources
PubMed2004

Comparison of 99mTc-DTPA and urea for measuring cefepime concentrations in epithelial lining fluid.

The efficacy of antimicrobial agents against pulmonary infections depends on their local concentrations in the lung. The aims of the present study were to: 1) compare technetium-99m diethylenetriaminepenta-acetic acid (99mTc-DTPA) and urea as markers of epithelial lining fluid (ELF) dilution for measuring ELF concentrations of pharmaceuticals; 2) quantify ELF cefepime concentrations in normal and injured lung; and 3) measure the increase in permeability to cefepime following oleic acid-induced acute lung injury. A modified bronchoalveolar lavage technique, based on equilibration of infused 99mTc-DTPA, was used to measure ELF volume. Cefepime was administered intravenously at steady plasma levels. Six serial bronchoalveolar lavages were performed 5 h after the beginning of infusion. ELF to plasma cefepime concentration ratios were 95 +/- 17 and 100 +/- 14.5% in normal and injured lung respectively. When urea was used as marker, cefepime concentration ratios were underestimated at 16.4 +/- 2.7 and 73.9 +/- 8.4% respectively. Cefepime blood/ airspace clearance increased from 3.8 +/- 0.7 micro x min(-1) in controls to 39.8 +/- 4.9 microL x min(-1) in acute lung injury. It was concluded that: 1) cefepime concentrations in epithelial lining fluid were in equilibrium with those in plasma in both normal and injured lung after 5 h at steady plasma concentrations; 2) epithelial lining fluid cefepime concentration by the urea method was much less underestimated in injured versus normal lung; and 3) acute lung injury induces a 10-fold elevation of cefepime blood/airspace clearance.

Analysis of Variance↗
PubMed2001

Co-amoxiclav pharmacokinetics during posttraumatic hemorrhagic shock.

OBJECTIVE: To determine the effects of severe trauma with hemorrhagic shock on amoxicillin and clavulanate concentrations in plasma and their pharmacokinetics. DESIGN: A prospective, open, descriptive study. SETTING: A 12-bed, adult surgical intensive care unit in a university-affiliated hospital in France. SUBJECTS: Subjects were 12 patients (10 men, 2 women) with severe trauma: median (range) Injury Severity Score, 38 (17-48); Acute Physiology and Chronic Health Evaluation II, 16 (7-38); Simplified Acute Physiology Score II, 41 (23-77). Also enrolled were 12 healthy volunteers who were matched on age (+/-5 yrs), gender, and body-surface area (+/-20 cm2). All the trauma patients suffered hemorrhagic shock defined as the association of at least one episode of systolic blood pressure <90 mm Hg and an intravascular volume expansion >2000 mL between trauma and surgery. INTERVENTION: Prophylactic perioperative administration of 2 g of amoxicillin and 0.2 g of clavulanate in combination during the first 12 hrs posttrauma in patients, and at the start of the pharmacokinetic study in volunteers. MEASUREMENTS AND MAIN RESULTS: Serial plasma samples (n = 13) were obtained after the first antibiotic administration to measure antibiotic levels by using high-performance liquid chromatography assays. Compared with volunteers, trauma patients had higher plasma amoxicillin and clavulanate concentrations, attributed to a reduction of the volume of distribution (p =.001 and p =.06, respectively) and, to a lesser extent, of the total body clearance (p =.09 and p =.20, respectively). Consequently, amoxicillin and clavulanate elimination half-lives were similar for the two groups of subjects. The interindividual variabilities for all the amoxicillin pharmacokinetic parameters were higher in patients. CONCLUSIONS: In trauma patients with hemorrhagic shock requiring surgery, the administration of 2 g of amoxicillin and 0.2 g of clavulanate seems adequate, according to the antibiotic concentrations observed in plasma for both drugs. However, further studies exploring antibiotic concentrations in tissues are warranted.

APACHE↗
PubMed2001

Sensitive and rapid method for the simultaneous quantification of the HIV-protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir in human plasma by reversed-phase liquid chromatography.

A rapid, sensitive, and specific liquid chromatography method for the simultaneous determination of four protease inhibitors (indinavir, nelfinavir, ritonavir, and saquinavir) in human plasma is described. After a liquid-liquid extraction with terbutyl methyl ether and a sequential washing of the reconstituted sample with hexane, protease inhibitors are separated on a phenyl column using a simple binary mobile phase of ammonium acetate buffer:acetonitrile (48:52) (pH = 7.5) with an ultraviolet detection at 260 nm. The standard curves are linear in the range 0.025-1 microg/mL for saquinavir, 0.1-4 microg/mL for indinavir and nelfinavir, and 0.25-10 microg/mL for ritonavir, with an average recovery ranging from 79% to 99%, and with both low interday and intraday coefficients of variation (<15%). This assay is simple, rapid (15-minute interval between runs) , and useful for therapeutic monitoring of the protease inhibitors on a routine basis.

Calibration↗
PubMed2001

Pharmacokinetics of oral acyclovir in neonates and in infants: a population analysis.

Acyclovir is approved for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections in children by the intravenous and oral routes. However, its use by the oral route in children younger than 2 years of age is limited due to a lack of pharmacokinetic data. The objectives of the present study were to determine the typical pharmacokinetics of an oral suspension of acyclovir given to children younger than 2 years of age and the interindividual variabilities in the values of the pharmacokinetic parameters in order to support the proposed dosing regimen (24 mg/kg of body weight three times a day for patients younger than 1 month of age or four times a day otherwise). Children younger than age 2 years with HSV or VZV infections were enrolled in a multicenter study. Children were treated for at least 5 days with an acyclovir oral suspension. Plasma samples were obtained at steady state, before acyclovir administration, and at 2, 3, 5, and 8 h after acyclovir administration. Acyclovir concentrations were measured by radioimmunoassay. The data were analyzed by a population approach. Data for 79 children were considered in the pharmacokinetic study (212 samples, 1 to 5 samples per patient). Acyclovir clearance was related to the estimated glomerular filtration rate, body surface area, and serum creatinine level. The volume of distribution was related to body weight. The elimination half-life decreased sharply during the first month after birth, from 10 to 15 h to 2.5 h. Bioavailability was 0.12. The interindividual variability was less pronounced when the parameters were normalized with respect to body weight. Hence, dosage adjustment by body weight is recommended for this population. Simulations showed that the length of time that acyclovir remains above the 50% inhibitory concentration during a 24-h period was more than 12 h for HSV but not for VZV. The proposed dosing regimen seems adequate for the treatment of HSV infections, while for the treatment of VZV infections, a twofold increase in the dose seems necessary for children older than age 3 months.

Acyclovir↗
PubMed2001

Individualising aminoglycoside dosage regimens after therapeutic drug monitoring: simple or complex pharmacokinetic methods?

Measurements of aminoglycoside concentration in serum are used to individualise dosage regimens (dose per administration and/or administration interval) with the goal of attaining the desired therapeutic range as quickly as possible. Therapeutic range is defined in terms of peak concentration (to monitor effectiveness) and trough concentration (to avoid toxicity). This article focuses on methods to individualise aminoglycoside dosage regimens in the context of extended dosage intervals. Simple pharmacokinetic methods involve linear dosage adjustment based on peak or trough concentrations or area under the concentration-time curve, or nomograms. The once daily aminoglycoside nomogram determines the dosage interval for aminoglycosides given as a fixed dose per administration, based on a single concentration measurement drawn 6 to 14 hours after the start of the first infusion. This is a preferred method because of its simplicity, strong pharmacodynamic rationale and prospective validation in a large population. However, it does not work when the fixed dose assumed is not relevant, for example for patients with burns, cystic fibrosis, ascites or pregnancy. Furthermore, it has not been validated in children. In these cases, a more sophisticated method is required. Complex pharmacokinetic methods require dedicated software. Non-Bayesian least-squares methods allow the optimisation of both the dose and the dosage interval, but require aminoglycoside concentrations from two or more samples taken in the post-distributive phase during a single dosage interval. With Bayesian least-squares methods, only one concentration measurement is required, although any number of samples can be taken into account. In the Bayesian maximum a posteriori (MAP) method, the parameter estimates are taken as the values corresponding to the maximum of the posterior density. In 'full' Bayesian approaches (also called stochastic control), all the information about the parameters revealed by the posterior distribution is taken into account, and the optimal regimen is found by minimising the expected value of the weighted sum of squared deviations between predicted and target concentrations. If the population model is reasonably well known, Bayesian methods (MAP or stochastic control) should be used because of their good predictive performance. Although only one concentration measurement is required, better precision is afforded by a two-sample strategy, preferably drawn 1 and 6 hours after the start of the first infusion. If the population model is not known, then the non-Bayesian least-squares method is the method of choice, because of its robustness and lack of requirement for prior information about the distribution of parameters in the population.

Aminoglycosides↗
PubMed2000

Ceftriaxone pharmacokinetics during iatrogenic hydroxyethyl starch-induced hypoalbuminemia: a model to explore the effects of decreased protein binding capacity on highly bound drugs.

BACKGROUND: Although various drugs used by anesthesiologists highly bind to plasma proteins, the impact of iatrogenically induced hypoproteinemia on their pharmacologic effects has never been investigated. The authors determined the pharmacokinetics of ceftriaxone, a cephalosporin that binds strongly to albumin in postsurgical patients with hydroxyethyl starch-induced hypoalbuminemia. METHODS: Eleven hypoalbuminemic (serum albumin < 25 g/l) patients and age (+/- 5 yr)-, sex-, and body surface area (+/- 10%)-matched healthy volunteers received a 2-g ceftriaxone dose infused over a 15-min period. Fourteen venous blood samples were collected during the 24-h study period. Free ceftriaxone concentrations were determined by ultrafiltration. Antibiotic concentrations in plasma and ultrafiltrate were measured by ion-paired reversed-phase chromatography. The pharmacokinetic parameters derived from total and free antibiotic concentrations were determined using a noncompartmental method. Data are expressed as median and range. RESULTS: The pharmacokinetic parameters derived from total ceftriaxone concentrations were similar for the two groups, except for the median corrected volume of distribution at steady state, which was increased (P = 0.05) to 0.18 l/kg (range, 0. 11-0.29 l/kg) in patients, compared with 0.15 l/kg (range, 0.13-0.22 l/kg) in volunteers. The area under the free ceftriaxone concentration-time curve was twice as high in patients as in volunteers (median 192, range 114-301 vs. median 122, range 84-169 h. mg-1. l-1;P = 0.03). Moreover, the free ceftriaxone concentration remained more than 4 mg/l during more time in patients (median, 16. 7; range, 12.6-21.4 vs. median, 11.1; range, 6.0-19.0 h; P = 0.03). CONCLUSIONS: Compared with healthy volunteers, patients with iatrogenic hypoalbuminemia have higher free ceftriaxone concentrations during the 24 h after antibiotic administration. This modification increases drug distribution into extravascular space and may enhance effectiveness.

Adolescent↗
PubMed2000

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.

Animals↗
PubMed2000

Clinical pharmacokinetics and pharmacodynamics of isepamicin.

Isepamicin is an aminoglycoside antibacterial with properties similar to those of amikacin, but with better activity against strains producing type I 6'-acetyltransferase. The antibacterial spectrum includes Enterobacteriaceae and staphylococci. Anaerobes, Neisseriaceae and streptococci are resistant. The lower and upper break-points are 8 and 16 mg/L. Like other aminoglycosides, isepamicin exhibits a strong concentration-dependent bactericidal effect, a long post-antibiotic effect (several hours) and induces adaptive resistance. Isepamicin is administered intravenously or intramuscularly at a dosage of 15 mg/kg once daily or 7.5 mg/kg twice daily. Isepamicin is not bound to plasma proteins, and it distributes in extracellular fluids and into some cells (outer hair cells, kidney cortex) by active transport. Isepamicin is not metabolised and is eliminated solely via the renal route with an elimination half-life (t 1/2 beta) of 2 to 3 hours in adults with normal renal function. The clearance of isepamicin is reduced in neonates, and 7.5 mg/kg once daily is recommended in children <16 days old. Clearance is also reduced in the elderly, but no dosage adjustment is required. In patients with chronic renal impairment, isepamicin clearance is proportional to creatinine clearance (CLCR); the recommended regimen is 8 mg/kg with an administration interval of 24 hours in moderate impairment, 48 hours in severe impairment, 72 hours for CL(CR) 0.6 to 1.14 L/h (10 to 19 ml/min) and 96 hours for CL(CR) 0.36 to 0.54 L/h (6 to 9 ml/min). In end-stage renal failure, isepamicin is eliminated by haemodialysis, but the administration interval should be determined by monitoring the plasma concentration. Compared with healthy volunteers, patients in the intensive care unit or with neutropenic cancer have an increased volume of distribution and a lower clearance, but the 15 mg/kg once daily regimen remains adequate. Isepamicin kinetics are linear in the range 7.5 to 25 mg/kg, so that dosage adjustments, if necessary, are straightforward. Isepamicin can induce nephro-, vestibulo- and oto-toxicity. However, animal and clinical studies show that isepamicin is one of the less toxic aminoglycosides. The usefulness of maintaining serum aminoglycoside concentrations within a therapeutic range remains controversial. With isepamicin, it is proposed to achieve a 1-hour concentration (30 minutes after a 30-minute infusion) >40 mg/L to maximise bactericidal efficacy, and a 'trough' concentration (at the end of the administration interval) <5 mg/L to minimise toxicity. These thresholds should be modified on an individual basis, considering covariates such as concomitant treatment, underlying disease, nature of bacterial strain and site of infection.

Adult↗
PubMed1999

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.

Adult↗
PubMed1999

Fluconazole, with or without dexamethasone for experimental cryptococcosis: impact of treatment timing.

The time of initiation of fluconazole treatment with or without dexamethasone, and the impact on mycological outcome and drug pharmacokinetics were assessed in a murine model of disseminated cryptococcosis. Non-infected mice and mice with disseminated cryptococcosis were given saline, dexamethasone, or fluconazole +/- dexamethasone, 1 or 8 days after infection. Cfus were counted in tissues, and fluconazole concentrations were determined in plasma and tissues by HPLC and a bioassay. Despite fluconazole tissue and plasma concentrations which were above the minimal inhibitory concentration, the numbers of cfus in brain and lung tissues were reduced after early (P = 0.002 and 0.04, respectively), but not after late fluconazole treatment. The administration of dexamethasone did not have a deleterious effect on the number of cfus, fluconazole pharmacokinetics or antifungal activity. In conclusion, the size of the fungal burden influences the effective level of fluconazole activity in lung and brain. These results strongly suggest that potential antifungal agents should be studied following both early and late administration in experimental cryptococcosis.

Animals↗
PubMed1999

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.

Amikacin↗
PubMed1999

Isepamicin in intensive care unit patients with nosocomial pneumonia: population pharmacokinetic-pharmacodynamic study.

A population approach was used to determine isepamicin pharmacokinetics in 196 intensive care unit patients treated for nosocomial pneumonia with isepamicin and a broad-spectrum beta-lactam. Patients were randomized in four groups with respect to the following isepamicin dosing regimens: (i) 15 mg/kg od for 5 days or (ii) 10 days, (iii) 25 mg/kg on the first day followed by 15 mg/kg od for 4 days or (iv) 9 days. A total of 1489 serum isepamicin concentrations were measured (median, eight per patient; range, 1-18). Mean +/- S.D. 1 h-peak levels at day 1 were 76 +/- 32 mg/L after the 25 mg/kg dose (n = 85) and 43 +/- 15 mg/L after the 15 mg/kg dose (n = 99). A bicompartmental model was fitted to the data by a mixed-effect modelling approach. Isepamicin clearance was related to age, bodyweight and serum creatinine level. Central volume of distribution was related to bodyweight. Pharmacokinetic parameters were independent of the dosage in the range 15-25 mg/kg and were not different in the patients treated for 5 or 10 days. Bayesian estimates of individual pharmacokinetic parameters were used to calculate various surrogate markers of isepamicin exposure to be tentatively correlated with clinical outcome and nephrotoxicity. No correlation was found between peak, AUC or their ratio with MIC and clinical efficacy. A weak correlation was found between the increase of serum creatinine level (day 1 versus day 5) and isepamicin 24 h trough level at day 1 (R2 = 0.10). These data do not favour a systematic therapeutic monitoring of isepamicin in intensive care unit patients, at least with the doses and antibiotic combinations used in this study.

Adult↗
PubMed1998

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.

Adult↗
PubMed1998

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.

Amikacin↗
PubMed1998

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.

Amikacin↗
PubMed1998

Population pharmacokinetic study of amikacin administered once or twice daily to febrile, severely neutropenic adults.

Once-daily (o.d.) administration of 20 mg of amikacin per kg of body weight to neutropenic patients has been validated by clinical studies, but amikacin pharmacokinetics have been documented only for the 7.5-mg/kg twice-daily (b.i.d.) regimen in this population. In order to determine in neutropenic patients (i) the influence of the dosing regimen on the kinetics of amikacin, (ii) the linearity of kinetics of amikacin in the range of 7.5 to 20 mg/kg, and (iii) the influence of patient characteristics on the disposition of amikacin and (iv) to provide a rationale for dosing recommendations, we evaluated the population pharmacokinetics of amikacin administered to 57 febrile neutropenic adults (neutrophil count, <500/mm3) being treated for a hematological disorder and receiving amikacin at 7.5 mg/kg b.i.d. (n = 29) or 20 mg/kg o.d. (n = 28) and administered intravenously over 0.5 h. A total of 278 blood samples were obtained (1 to 14 samples per patient) during one or several administration intervals (1 to 47). Serum amikacin levels were measured by the enzyme-multiplied immunoassay technique. A mixed-effect modeling approach was used to fit a bicompartmental model to the data (NONMEM software). The influences of the dosing regimen and the demographic and biological indices on the pharmacokinetic parameters of amikacin were evaluated by the maximum-likelihood ratio test on the population model. The dosing regimen had no influence on amikacin pharmacokinetic parameters, i.e., the kinetics of amikacin were linear over the range of 7.5 to 20 mg/kg. Amikacin elimination clearance (CL) was only correlated with creatinine clearance or its covariates, namely, sex, age, body weight, and serum creatinine level. The interindividual variability of CL was 21%, while those of the central volume of distribution, the distribution clearance, and the tissue volume of distribution were 15, 30, and 25%, respectively. On the basis of the expected distribution of amikacin concentrations in this population, dosing recommendations as a function of creatinine clearance (CL[CR]) are proposed: for patients with normal renal function (CL[CR] of 80 to 130 ml/min), 20 mg/kg o.d. is recommended, whereas for patients with severe renal impairment (CL[CR], 10 to 20 ml/min), a dosage of 17 mg/kg every 48 h is recommended.

Adolescent↗
PubMed1998

Analysis of the pharmacokinetic interaction between cephalexin and quinapril by a nonlinear mixed-effect model.

Oligopeptidic drugs such as beta-lactams and angiotensin-converting enzyme inhibitors share the same carriers in humans and animals, which results in possible pharmacokinetic interactions. To model such interactions, the effects of quinapril on cephalexin pharmacokinetics were investigated in rats. Blood cephalexin concentrations were measured by liquid chromatography, and the data were analyzed by a noncompartmental method and by fitting a bicompartmental model by a nonlinear mixed-effect modeling approach. Five groups of eight rats were examined. In the first three groups, cephalexin elimination kinetics after intra-arterial administration alone or in combination with quinapril given by the parenteral or the oral route were studied, and the occurrence of a pharmacokinetic interaction was not revealed. The absence of an effect of quinapril on cephalexin elimination after parenteral administration might be explained either by the higher affinity of cephalexin for the renal anionic transport system than that of quinapril or by the much higher concentrations of cephalexin than those of quinapril. In the last two groups, cephalexin was administered by the oral route alone or in combination with quinapril. The mean area under the concentration-time curve (AUC) for cephalexin was increased by ca. 30% by coadministration of quinapril (40.1 versus 31.4 mg.h/liter; P = 0.04). The mean elimination clearance of cephalexin was significantly decreased by quinapril, from 0.81 to 0.64 liter/h/kg of body weight (P < 0.05), probably by competitive inhibition of cephalexin secretion at the tubular level. The mean absorption rate constant of cephalexin was significantly lowered by quinapril (from 0.249 to 0.177 h-1; P < 0.01), without modification of the extent of absorption (89%). This pharmacokinetic interaction could be explained by competitive inhibition of cephalexin active transport by quinapril at the intestinal level.

Angiotensin-Converting Enzyme Inhibitors↗