Doses Of Ceftazidime Research Articles

Pharmacokinetic Profiles of Ceftazidime after Intravenous Administration in Patients Undergoing Automated Peritoneal Dialysis

The pharmacokinetics (PK) of ceftazidime after intravenous (i.v.) administration during automated peritoneal dialysis (APD) and their dependence on peritoneal membrane transport are the targets of the present study. Eleven patients receiving a single i.v. dose of ceftazidime (15 mg/kg of body weight) (seven males, median [interquatile] age, 59 [36 to 62]) were recruited. Serum and dialysate samples were collected at the beginning, middle, and end of each of the five dwells during a 24-h period, with dwells 1, 2, and 3 using an automated cycler (designated on-cycler) and dwells 4 and 5 being manual exchanges (designated off-cycler), together with urine collection during the same period. Population PK analysis was employed to estimate the PK parameters. Peritoneal equilibration tests were performed for all patients, and correlations between peritoneal clearance (CL(PD)) for ceftazidime and dialysate-to-plasma ratios for creatinine (D/P(cr)) were obtained using the Spearman's product correlation coefficient (ρ). Ceftazidime renal clearance (CL(renal)) was 0.052 ml/min/kg, and CL(PD) was 0.063 ± 0.050 ml/min/kg. CL(PD) for on- and off-cycler were 0.071 and 0.058 ml/min/kg (P = 0.164), respectively. A significant correlation between CL(PD) and D/P(cr) was observed, with one outlier excluded, suggesting that CL(PD) for ceftazidime during APD is dependent upon the peritoneal small-solute transport rate. A model prediction yielded adequate serum and dialysate concentrations of ceftazidime throughout a 24-h period for sensitive organisms (MIC, 8 μg/ml) by either i.v. (at 15 mg/kg) or intraperitoneal (i.p.; at 20 mg/kg) administration during off-cycler dwells. The present study suggests that the i.v. administration of ceftazidime at 15 mg/kg or i.p. administration of ceftazidime at 20 mg/kg during a long dwell every 24 h can be recommended for treating systemic or intraperitoneal infections of APD patients.

Influence of Pluronic® F68 on Ceftazidime Biological Activity in Parenteral Solutions

β-Lactam antimicrobials are known to have a low concentration/therapeutic response. However, extending the period in which β-lactam are free in the plasma does directly influence therapeutic outcomes. The objective of this study was to evaluate the influence of Pluronic® F68 on the antimicrobial activity of ceftazidime when admixed with aminophylline in parenteral solutions by the evaluation of its minimal inhibitory concentration (MIC) within 24 h. Ceftazidime, aminophylline, and Pluronics® F68 were evaluated using the MIC method against Escherichia coli and Pseudomonas aeruginosa, with these compounds individually and associated in the same parenteral solutions. When Pluronics® F68 was admixtured with ceftazidime alone or with ceftazidime and aminophylline, it was possible to observe lower MIC values not only at 24 h but also at 0 h for both microorganisms. This indicates that Pluronics® F68 may be able to enhance ceftazidime antimicrobial activity in the presence or absence of aminophylline. This fact suggests that Pluronics® F68 can be applied to allow the administration of ceftazidime under continuous infusion in parenteral solutions, beneficiating hospital pharmacotherapy. It may also be possible to reduce ceftazidime doses in formulations achieving the same therapeutic results.

Gamma Interferon Supplementation for Melioidosis

Mortality from melioidosis approaches 50% despite appropriate antimicrobial therapy (4), and new approaches are urgently needed. Burkholderia pseudomallei is an intracellular pathogen, and gamma interferon (IFN-γ)-mediated responses are essential for the normal host response to melioidosis (7). Plasma levels of IFN-γ are already high in patients with acute melioidosis (2), but it is tempting to speculate that a relative IFN-γ deficiency exists. The finding by Propst et al. that IFN-γ supplementation confers a survival benefit in murine melioidosis (6) is exciting, as there already exists an FDA-licensed preparation of IFN-γ (Actimmune, InterMune Inc.; >$300/dose). The up-front cost is high, but this was not a barrier to evaluating granulocyte colony-stimulating factor (G-CSF) in a clinical trial (1). We are therefore motivated to outline two issues that remain to be addressed before IFN-γ supplementation can be transferred from bench to bedside. In the mouse experiments, the investigators deliberately selected a subtherapeutic ceftazidime dose (50 mg/kg of body weight/day) when a more appropriate dose might be 1,200 mg/kg/day (5). While we agree with the authors' sentiment that “full-dose therapy should be capable of generating even greater protection,” the clinical question is whether IFN-γ supplementation might improve survival when combined with the current recommended antimicrobial therapy, and there is no clinical situation in which low-dose ceftazidime would be used. Had full-dose ceftazidime been used, it is possible that the bacterial burden may have been so reduced by ceftazidime alone that no additional effect would be seen with supplemental IFN-γ. When contemplating a clinical trial of IFN-γ therapy, we would prefer to see first evidence from studies using full-dose ceftazidime, and it would be reassuring to hear from the authors that these studies are in progress. Should no effect be seen on mortality (e.g., because all mice survive), then differences in bacterial clearance rates would still be relevant, because the median fever clearance time in patients with melioidosis is 9 days despite ceftazidime, and intravenous antimicrobial therapy must sometimes be continued for >1 month. The issue of diagnosis could not have been addressed by this study but relates directly to the clinical implementation of IFN-γ therapy. Acute melioidosis has no clinical features that allow it to be reliably distinguished from other causes of severe sepsis, except isolation of B. pseudomallei, which means a delay of 24 to 48 h. Around half the patients with melioidosis die within 48 h of presentation, so therapy is often begun on clinical suspicion alone (4). The result is that less than half of all patients treated empirically for melioidosis have culture confirmation of their disease (8). IFN-γ supplementation started prior to microbiological confirmation inevitably means the inadvertent treatment of other infections. Aside from an added financial burden, the effect of IFN-γ supplementation in other causes of sepsis is unclear. In a murine model of polymicrobial sepsis, IFN-γ supplementation increased mortality in a dose-dependent fashion (3), which means that pending improvements in the diagnosis of melioidosis, any benefit of IFN-γ supplementation may be negated by a deleterious effect of IFN-γ on other causes of community-acquired sepsis.

Prospective Determination of Serum Ceftazidime Concentrations in Intensive Care Units

The purpose of this study was to assess the value of a serum assay for ceftazidime (CAZ) in patients in the intensive care unit (ICU) of the Saint-Etienne University Teaching Hospital and in other ICUs in the region to optimize therapy. Between November 1, 2005, and February 29, 2008, for patients hospitalized in ICUs not on dialysis and undergoing continuous CAZ infusion, serum assay of the antibiotic was performed 36 to 48 hours after the start of treatment using a single serum sample. The target serum CAZ concentration was 40 +/- 10 mg/L with a concentration/minimum inhibitory concentration ratio of 5 or greater x minimum inhibitory concentration of CAZ when a strain was isolated. Serum CAZ concentration was determined in 92 patients (28 females, 64 males) receiving CAZ by continuous infusion. The mean age was 66 years (range, 19-89 years) and the mean weight was 73 kg (range, 33-122 kg). The CAZ dose was between 1 g and 6 g/24 hours. The mean serum CAZ concentration was 46.9 mg/L (range, 7.4-162.3 mg/L). Serum CAZ concentrations were as follows: 30 to 50 mg/L in 35.9% of patients, less than 30 mg/L in 36.9%, and greater than 50 mg/L in 27.2%. Infection was documented in 51 patients, with 42 strains of Pseudomonas aeruginosa being detected. The serum concentration/minimum inhibitory concentration ratio was 5 or greater for 84.3%. Antibiotic dosage was adjusted based on the CAZ assay results. Our study suggests that CAZ measurement is needed in ICUs to achieve adequate CAZ concentrations to avoid treatment toxicity and to achieve efficacy as rapidly as possible, particularly in strains having limited susceptibility to antibiotics.

Immunotherapy Markedly Increases the Effectiveness of Antimicrobial Therapy for Treatment ofBurkholderia pseudomalleiInfection

Burkholderia pseudomallei is a soil bacterium that is endemic in southeast Asia and northern Australia and that can cause both acutely lethal pneumonia and chronic systemic infections in humans. The effective treatment of infection with B. pseudomallei requires rapid diagnosis and prolonged treatment with high doses of antimicrobials, and even with appropriate antibiotic therapy, patient relapses are common. Thus, new approaches to the treatment of B. pseudomallei infections are needed. In the present study, we asked whether active immunotherapy with gamma interferon (IFN-gamma), a key cytokine regulating the intracellular replication of B. pseudomallei, could increase the effectiveness of conventional antimicrobial therapy for B. pseudomallei infection. Macrophage infection assays and in vivo pulmonary challenge models were used to assess the inhibitory effects of combined treatment with IFN-gamma and ceftazidime on B. pseudomallei infection. We found that treatment with even very low doses of IFN-gamma and ceftazidime elicited strong synergistic inhibition of B. pseudomallei growth within infected macrophages. In vivo, active immunotherapy markedly potentiated the effectiveness of low-dose ceftazidime therapy for the treatment of infected mice in a pulmonary challenge model of B. pseudomallei. Combined treatment was associated with a significant reduction in the bacterial burden and a significant lessening of bacterial dissemination. We concluded, therefore, that immunotherapy with either endogenous or exogenous IFN-gamma could significantly increase the effectiveness of conventional antimicrobial therapy for the treatment of acute B. pseudomallei infection.

Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock

IntroductionAltered pharmacokinetics (PK) in critically ill patients can result in insufficient serum β-lactam concentrations when standard dosages are administered. Previous studies on β-lactam PK have generally excluded the most severely ill patients, or were conducted during the steady-state period of treatment. The aim of our study was to determine whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem would result in adequate serum drug concentrations in patients with severe sepsis and septic shock.MethodsOpen, prospective, multicenter study in four Belgian intensive care units. All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom treatment with the study drugs was indicated, were included. Serum concentrations of the antibiotics were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5 and 6 or 8 hours after administration.Results80 patients were treated with piperacillin-tazobactam (n = 27), ceftazidime (n = 18), cefepime (n = 19) or meropenem (n = 16). Serum concentrations remained above 4 times the minimal inhibitory concentration (T > 4 × MIC), corresponding to the clinical breakpoint for Pseudomonas aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for 57% of the dosage interval for meropenem (target MIC = 8 μg/mL), 45% for ceftazidime (MIC = 32 μg/mL), 34% for cefepime (MIC = 32 μg/mL), and 33% for piperacillin-tazobactam (MIC = 64 μg/mL). The number of patients who attained the target PK profile was 12/16 for meropenem (75%), 5/18 for ceftazidime (28%), 3/19 (16%) for cefepime, and 12/27 (44%) for piperacillin-tazobactam.ConclusionsSerum concentrations of the antibiotic after the first dose were acceptable only for meropenem. Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime may, therefore, be insufficient to empirically cover less susceptible pathogens in the early phase of severe sepsis and septic shock.

Use of a low-dose steroid as an adjunct in the treatment, in mice, of severe sepsis caused byBurkholderia pseudomallei

Human melioidosis caused by Burkholderia pseudomallei is a severe septic disease that is associated with high mortality, even under appropriate antibiotic treatment. The therapeutic effects of low-dose hydrocortisone plus ceftazidime, and of ceftazidime alone, have recently been investigated in the treatment of acute, severe sepsis caused by B. pseudomallei, both in normal BALB/c mice and in BALB/c mice with streptozotocin-induced diabetes. The mice were infected and then treated intravenously, from day 1 or day 2 post-infection, with saline (as a control, given twice daily for 10 days), low-dose hydrocortisone (given in twice-daily doses of 5 mg/kg, for 5 days) plus ceftazidime (given in twice-daily doses of 1200 mg/kg, for 10 days), or the same doses of ceftazidime alone. Although the infected, untreated mice all died within 14 days, almost all of the treated animals were still alive at the end of the follow-up, 30 days post-infection. The addition of the steroid appeared to have no benefit, with bacterial loads and plasma concentrations of tumour necrosis factor, aspartate aminotransferase, alanine aminotransferase and creatinine decreasing similarly in all the treated groups. The infected diabetic mice given hydrocortisone-ceftazidime from day 1 (but not those given just ceftazidime from day 1) showed an increase in their blood glucose concentrations. When infected mice were treated with the low-dose steroid and lower doses of the antibiotic (in twice-daily doses of 120-600 mg/kg), the steroid not only offered no apparent benefit but seemed to reduce survival. It therefore appears that low-dose hydrocortisone, as an adjunct to antibiotic treatment, does not provide benefit in the treatment of murine melioidosis and may have negative effects on human cases of the disease who have diabetes mellitus.

In vitro AN69 and Polysulphone Membrane Permeability to Ceftazidime and in vivo Pharmacokinetics during Continuous Renal Replacement Therapies

Background: Ceftazidime is a third-generation cephalosporin almost entirely eliminated by glomerular filtration and dose reductions are essential in patients with renal impairment. The physicochemical and pharmacokinetic properties of ceftazidime make it susceptible to be eliminated by continuous renal replacement therapies (CRRT), but there is little clinical information to guide the correct administration in patients undergoing these techniques. Methods: In vitro procedures were carried out in three different fluids, using AN69 or polysulphone membranes. Four patients entered the in vivo study. Two patients received 1,000 mg every 6 h and the other two 2,000 mg every 6 h. Concentrations of ceftazidime were measured by high-performance liquid chromatography. Results: No differences were detected in thesieving coefficients (Sc) or saturation coefficients (Sa)between membranes during continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHD). Sc-Sa values were close to 1 when Ringer’s lactate was used as ceftazidime vehicle, but were lower in plasma samples (p < 0.05). In patients, the Sc-Sa was 0.93 ± 0.06 and correlated well with the unbound fraction (0.86 ± 0.08). The contribution of CRRT to ceftazidime clearance was higher in anuric patients than in nonanuric patients. Conclusions: No differences were shown in vitro in the Sc obtained with both membranes during CVVH or the Sa obtained during CVVHD. The contribution of clearance by CRRT to total clearance is clearly dependent on the renal function. The administration of ceftazidime every 6 h could be associated with unnecessarily high trough levels which increase the risk of drug nephrotoxicity. Nonanuric patients undergoing CRRT need higher ceftazidime doses to reach adequate plasma concentrations against pathogens isolated in the critically ill.

Intermittent administration of ceftazidime to burns patients: influence of glomerular filtration

The pharmacokinetics of ceftazidime, the antibiotic of choice for treating acute P. aeruginosa infections, may be modified in burns patients. The aim of this study was to identify the factors causing variations in the serum antibiotic concentrations in bums patients. 30 patients with serious burns were randomly divided into two groups. Group 1 received a dose of ceftazidime of 2 x 3 g/24 hours. The second group received the same dose but divided into 6 administrations. Blood samples were taken at 24 (M1) and 48 hours (M2) after the start of treatment and the peak and trough serum concentrations of ceftazidime measured by HPLC. Depending on the results, frequency and/or dose was modified to obtain trough concentrations (Cmin) equal to 16 mg/l, i.e. 4 times the MIC. Either the same dose was maintained, but mostly divided up, or it was increased to 1 g x 8 administrations or it was decreased to 1 g x 4 or 1 g x 3. The serum concentrations of ceftazidime obtained were analyzed taking into account the characteristics of the burns patients (multivariate correlation). From the first sample (M1) Cmin was lower than the target concentration in 50% of the patients in Group 1 and 20% in Group 2. The modification of the dosing regimen put into place after the first analysis, led to the patients being further divided into four groups before the second blood sampling. Finally, 5 patients ended up in Group 1. In all patients and for all administration times, a negative correlation was found between Cmin and the creatinine clearance, calculated by using Cockcroft's formula. This study highlights the peculiarities of ceftazidime pharmacokinetics seen in burns patients with high interindividual variability. Based on Cmin monitoring and a predefined therapeutic range, dose adjustment was often required. Ceftazidime clearance is correlated with creatinine clearance (Cockcroft's formula), suggesting that this parameter could be used for a priori or a posteriori dose individualization. To respect the summary of the product characteristics (SPC) and reduce the variability in trough concentrations, the dose should be fractionated (1 g x 6) over a 24-hour period or even given as a continuous infusion. Trough concentrations must be evaluated to adapt the dosage regimen to attain target concentrations of 4 x the MIC.

Role of ceftazidime dose regimen on the selection of resistant Enterobacter cloacae in the intestinal flora of rats treated for an experimental pulmonary infection

The effect of ceftazidime dosing increments and frequency of dosing on the selection of ceftazidime-resistant Enterobacter cloacae in the intestine was studied in rats, during treatment of a pulmonary infection caused by Klebsiella pneumoniae. Rats with pulmonary infection (n = 10 per group) received therapy with doses of ceftazidime at 3.1 to 400 mg/kg per day at a frequency of every 6,12 or 24 h for 18 days, starting 24 h after bacterial inoculation of the lung. Emergence of resistance in intestinal E. cloacae was monitored by culturing fresh stool specimens at days 0, 8, 15, 22, 29, 36 and 43 on agar plates with (6.4 mg/L) and without ceftazidime. Pharmacodynamic indices and time within the mutant selection window (MSW) were assessed in infected rats for each regimen. Ceftazidime-resistant E. cloacae mutants were characterized by determination of the beta-lactamase activity under cefoxitin-induced and non-induced conditions. A reduction of intestinal ceftazidime-susceptible E. cloacae was observed and showed a significant correlation with the fAUC/MIC at days 8, 15 and 22 and with the fCmax on days 8, 15, 22, 29 and 36. More rats treated with 12-25 and 50-100 mg/kg per day every 6 h were found colonized with ceftazidime-resistant E. cloacae mutants than animals treated every 12 h or every 24 h. The proportion of rats colonized with ceftazidime-resistant E. cloacae mutants at days 15, 36 and 43 correlated with the time during which ceftazidime plasma concentrations were within the boundaries of the MSW. Only at day 15 was a correlation demonstrated between the fCmax and significantly fewer rats colonized with ceftazidime-resistant E. cloacae. Ceftazidime-resistant E. cloacae mutants (MIC >or= 128 mg/L) were characterized as stable derepressed mutants. Colonization with stable derepressed ceftazidime-resistant E. cloacae mutants particularly occurred when rats were exposed to moderate doses of ceftazidime (12-25 or 50-100 mg/kg per day) administered every 6 h. Emergence of resistance was correlated with time within the MSW.

Disposition of Ceftazidime After Intraperitoneal Administration in Adolescent Patients Receiving Continuous Cycling Peritoneal Dialysis

Peritonitis is the single most common complication in children maintained on continuous cycling peritoneal dialysis (CCPD) and a significant cause of morbidity. Recent consensus guidelines for the treatment of peritonitis in children receiving peritoneal dialysis recommend the combined intraperitoneal administration of ceftazidime with either a first-generation cephalosporin or vancomycin. The objective of this study is to determine whether a continuous maintenance dose of intraperitoneal ceftazidime in the absence of a loading dose would maintain adequate serum and dialysate concentrations to be effective in the treatment of peritonitis. Five ambulatory patients on CCPD therapy were studied with continuous intraperitoneal administration of ceftazidime (125 mg/L). Blood, dialysate, and urine samples were collected at specified intervals during a 24-hour period. Ceftazidime concentrations were measured by using a high-performance liquid chromatography assay. Mean serum concentrations at completion of the short rapid cycles and at 24 hours were 28.92 +/- 13.64 and 23.92 +/- 11.93 microg/mL, respectively. Serum bioavailability at 24 hours was 74% +/- 6%. Mean dialysate concentrations at completion of the short rapid cycles and at 24 hours were 87.43 +/- 19.18 and 32.06 +/- 6.27 microg/mL, respectively. All 5 patients achieved serum and dialysate ceftazidime concentrations greater than the mean inhibitory concentration within 4 hours. In adolescent patients on CCPD therapy, a continuous maintenance dose of intraperitoneal ceftazidime in the absence of a loading dose achieves serum and dialysate levels greater than the mean inhibitory concentration of sensitive organisms within 4 hours that persist for 24 hours.

Retinal Toxicity of Intraocular Vancomycin and Ceftazidime in Vitrectomized Rabbit Eyes

The purpose of this study was to evaluate the retinal toxicity of vancomycin and ceftazidime combined into an infusion solution that was intraoculary given after or during vitrectomy. Forty albino rabbits were divided into 4 groups of 10 each. Vitrectomized right eyes of groups 1, 2, and 3 were given recommended doses of vancomycin and ceftazidime alone or combined, while right eyes in the fourth group were vitrectomized using an infusion solution to which was added ceftazidime and vancomycin combination. Toxicity was tested with electroretinography (ERG) and light microscopy. ERG and light microscopy did not show any toxicity signs associated with vancomycin or ceftazidime alone or with combined therapy. Vancomycin and/or ceftazidime can reliably and effectively be used combined in an infusion solution at recommended doses after and during vitrectomy. This treatment modality does not have any toxic effects to retinal structures and is an alternative method to separate injections of the two antimicrobial agents.

Continuous infusion of ceftazidime in critically ill patients undergoing continuous venovenous haemodiafiltration: pharmacokinetic evaluation and dose recommendation

IntroductionIn seriously infected patients with acute renal failure and who require continuous renal replacement therapy, data on continuous infusion of ceftazidime are lacking. Here we analyzed the pharmacokinetics of ceftazidime administered by continuous infusion in critically ill patients during continuous venovenous haemodiafiltration (CVVHDF) in order to identify the optimal dosage in this setting.MethodSeven critically ill patients were prospectively enrolled in the study. CVVHDF was performed using a 0.6 m2 AN69 high-flux membrane and with blood, dialysate and ultrafiltration flow rates of 150 ml/min, 1 l/hour and 1.5 l/hour, respectively. Based on a predicted haemodiafiltration clearance of 32.5 ml/min, all patients received a 2 g loading dose of ceftazidime, followed by a 3 g/day continuous infusion for 72 hours. Serum samples were collected at 0, 3, 15 and 30 minutes and at 1, 2, 4, 6, 8, 12, 24, 36, 48 and 72 hours; dialysate/ultrafiltrate samples were taken at 2, 8, 12, 24, 36 and 48 hours. Ceftazidime concentrations in serum and dialysate/ultrafiltrate were measured using high-performance liquid chromatography.ResultsThe mean (± standard deviation) elimination half-life, volume of distribution, area under the concentration-time curve from time 0 to 72 hours, and total clearance of ceftazidime were 4 ± 1 hours, 19 ± 6 l, 2514 ± 212 mg/h per l, and 62 ± 5 ml/min, respectively. The mean serum ceftazidime steady-state concentration was 33.5 mg/l (range 28.8–36.3 mg/l). CVVHDF effectively removed continuously infused ceftazidime, with a sieving coefficient and haemodiafiltration clearance of 0.81 ± 0.11 and 33.6 ± 4 mg/l, respectively.ConclusionWe conclude that a dosing regimen of 3 g/day ceftazidime, by continuous infusion, following a 2 g loading dose, results in serum concentrations more than four times the minimum inhibitory concentration for all susceptible pathogens, and we recommend this regimen in critically ill patients undergoing CVVHDF.

Pharmacokinetics of Intraperitoneal Cefazolin and Ceftazidime Coadministered to CAPD Patients

Guidelines for empiric treatment of PD-related peritonitis published in 2000 recommend concurrent intraperitoneal (IP) cefazolin and ceftazidime. The pharmacokinetics (PK) of these agents combined have not been studied. This study was designed to determine the PK of combined IP cefazolin and ceftazidime in CAPD patients. Prospective PK study in seven non-infected CAPD patients. Patients had a peritoneal equilibration test (PET), then received one IP dose of cefazolin and ceftazidime (15 mg/kg each) co-administered over a 4-hour dwell, then performed three CAPD exchanges over the next 16 hours. Serum and dialysate samples collected over the 20-hour study period were assayed for drug concentrations by HPLC. PK parameters. Correlations were tested between PET and PK parameters using the Pearson-product correlation coefficient. Serum cefazolin and ceftazidime levels exceeded the minimum inhibitory concentrations for susceptible organisms (8 mg/L) throughout the 20 hour study period. Mean cefazolin and ceftazidime PK parameters included: bioavailability, 71% and 63%; elimination rate constant, 0.031 and 0.045 h -1 ; total clearance, 5.8 and 16.0 ml/min; peritoneal clearance, 1.6 and 3.9 ml/min; renal clearance, 2.3 and 3.9 ml/min, respectively. Predictive equations suggest that 1000 mg IP of cefazolin and of ceftazidime every 24 hours would produce average steady-state trough serum cefazolin and ceftazidime concentrations of 70 +/- 52 mg/L and 17 +/- 7 mg/L, respectively. There was no correlation between PET and PK parameters. Co-administration did not adversely affect the PK of either agent. IP cefazolin and ceftazidime (15 mg/kg) produced adequate serum and dialysate concentrations in CAPD patients for 20 hours. PK predictions suggest that most patients would achieve adequate cefazolin and ceftazidime concentrations with 1000 mg IP once-daily. Anuric patients and those with significant residual renal function may require a more individualized approach.

Simulation of Antibiotic Pharmacodynamic Exposure for the Empiric Treatment of Nosocomial Bloodstream Infections: A Report from the OPTAMA Program

We developed a model to predict the pharmacodynamic exposure of antibiotics against bacteria commonly implicated in nosocomial bloodstream infections to determine which dosage regimens would provide the greatest likelihood of obtaining a bactericidal effect. Pharmacodynamic exposures were simulated for 5000 subjects receiving standard doses of ceftazidime, cefepime, piperacillin/tazobactam, meropenem, imipenem, or ciprofloxacin. Exposures were indexed to the MICs of bacteria weighted by their prevalence in causing nosocomial bloodstream infections, derived from 2002 SENTRY data. Enterococci were excluded. MIC data were derived from the 2003 Meropenem Yearly Surveillance Test Information Collection resistance study. The probabilities of achieving bactericidal exposures (ie, target attainment) for each antibiotic regimen were compared. The effect of increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) on attainment of bactericidal targets was tested. All dosage regimens except ciprofloxacin and ceftazidime 1 g q8h achieved >90% likelihood of bactericidal exposure. The rank order of target attainment was as follows: imipenem 500 mg q6h, 100.0%; imipenem 1 g q8h, 99.9%; cefepime 2 g q12h, 99.4%; meropenem 1 g q8h, 98.4%; cefepime 1 g q12h, 98.2%; piperacillin/tazobactam 3.375 g q6h, 97.9%; piperacillin/tazobactam 4.5 gq8h, 95.0%; ceftazidime 2 g q8h, 94.2%; ceftazidime 1 g q8h, 71.7%; ciprofloxacin 400 mg q8h, 63.3%; and ciprofloxacin 400 mg q12h,63.0%. Target attainments dropped to <90% for all agents when MRSA was modeled at > or =10% prevalence. The results of this model analysis suggest that standard doses of the carbapenems, piperacillin/tazobactam, and cefepime, and higher doses of ceftazidime, may provide optimal likelihood of achieving bactericidal exposure against pathogens implicated in nosocomial bloodstream infections, excluding MRSA and enterococci. When MRSA rates are > or =10%, therapy with an antibiotic that has activity against this phenotype should be empirically initiated.

A retrospective analysis using Monte Carlo simulation to evaluate recommended ceftazidime dosing regimens in healthy volunteers, patients with cystic fibrosis, and patients in the intensive care unit

Background:Over the past decades, the relationship between the pharmacokinetic (PK) properties of antibiotics, MICs, and clinical effects has been increasingly well understood. Interpatient variability in the PK profile, however, has only recently been recognized as a major factor in predicting the outcome in individual patients and establishing breakpoints for clinical susceptibility. Most predictions to date have used data from healthy volunteers. Objective:The purpose of this study was to perform Monte Carlo simulations of the PK/pharmacodynamic relationships of ceftazidime to assess whether the probability of target attainment (PTA) differed significantly between 3 distinct populations. To that end, population PK models of ceftazidime were developed for the 3 populations. Methods:Serum concentration-time data from earlier studies in healthy volunteers (n = 8), patients with cystic fibrosis (CF) (n = 17), and patients in the intensive care unit (ICU) (n = 6) were used to obtain population PK parameter estimates and covariance matrices using the nonparametric adaptive grid program. The PTA for each group was obtained using 10,000 patient simulations for dosing regimens of 1000 and 2000 mg q8h over a range of MICs and percentages of time that concentrations of unbound drug remained above the MIC (%T>MIC). Results:The relationship between the MIC and the population mean %T>MIC, as well as the PTA profiles, differed markedly between the 3 groups as a result of both differences and variations in Vd and Cl. Breakpoints based on a 100% PTA for a %T>MIC of 60% were ≤4, 0.5, and 0.5 mg/L in healthy volunteers, patients with CF, and patients in the ICU, respectively. However, when PTA values between 90% and 100% were reevaluated and differences in clinical dosing regimens were accounted for, the resulting breakpoints were identical in the 3 groups. Conclusions:PK parameter estimates for ceftazidime based on data from a small group of healthy volunteers resulted in a clinical susceptibility breakpoint comparable to those for patients with CF and patients in the ICU. Based on the study findings, this breakpoint would be ≤4 mg/L. Patients suspected of having unusually high rates of clearance should be monitored closely.

Intravenous versus Nebulized Ceftazidime in Ventilated Piglets with and without Experimental Bronchopneumonia

Lung deposition of intravenous cephalosporins is low. The lung deposition of equivalent doses of ceftazidime administered either intravenously or by ultrasonic nebulization using either nitrogen-oxygen or helium-oxygen as the carrying gas of the aerosol was compared in ventilated piglets with and without experimental bronchopneumonia. Five piglets with noninfected lungs and 5 piglets with Pseudomonas aeruginosa experimental bronchopneumonia received 33 mg/kg ceftazidime intravenously. Ten piglets with noninfected lungs and 10 others with experimental P. aeruginosa bronchopneumonia received 50 mg/kg ceftazidime by ultrasonic nebulization. In each group, the ventilator was operated in half of the animals with a 65%/35% helium-oxygen or nitrogen-oxygen mixture. Animals were killed, and multiple lung specimens were sampled for measuring ceftazidime lung tissue concentrations by high-performance liquid chromatography. As compared with intravenous administration, nebulization of ceftazidime significantly increased lung tissue concentrations (17 +/- 13 vs. 383 +/- 84 microg/g in noninfected piglets and 10 +/- 3 vs. 129 +/- 108 microg/g in piglets with experimental bronchopneumonia; P < 0.001). The use of a 65%/35% helium-oxygen mixture induced a 33% additional increase in lung tissue concentrations in noninfected piglets (576 +/- 141 microg/g; P < 0.001) and no significant change in infected piglets (111 +/- 104 microg/g). Nebulization of ceftazidime induced a 5- to 30-fold increase in lung tissue concentrations as compared with intravenous administration. Using a helium-oxygen mixture as the carrying gas of the aerosol induced a substantial additional increase in lung deposition in noninfected piglets but not in piglets with experimental bronchopneumonia.

Intraventricular Tobramycin in a Premature Infant with Pseudomonas Meningitis

A 38-week postconceptional age (29-week gestational age) infant required the placement of an Ommaya reservoir following a grade IV intraventricular hemorrhage and progressive hydrocephalus. At 70 days of age, a cerebrospinal fluid (CSF) culture was positive for Pseudomonas aeruginosa and the infant was empirically treated with age-appropriate parenteral doses of ceftazidime and gentamicin. This antibiotic regimen was changed to meropenem and tobramycin following the results of sensitivity reports. The infection failed to respond despite aggressive systemic dosing of antibiotics and removal of the Ommaya reservoir. Intraventricular injections of tobramycin were added to the systemic antibiotic regimen at a dose of 2 mg daily with subsequent doses adjusted to maintain trough concentrations in the CSF of 20-30 μg/mL. The CSF was sterilized after three days of intraventricular injections. The infant completed seven days of intraventricular tobramycin plus a 24-day regimen of systemic antibiotics. No acute complications were noted with the addition of intraventricular injections.

In vitro and in vivo activities of AM-112, a novel oxapenem.

AM-112 [(1'R,5R,6R)-3-(4-amino-1,1-dimethyl-butyl)-6-(1'-hydroxyethyl)oxapenem-3-carboxylate] is a novel oxapenem compound which possesses potent beta-lactamase-inhibitory properties. Fifty-percent inhibitory concentrations (IC(50)s) of AM-112 for class A enzymes were between 0.16 and 2.24 micro M for three enzymes, compared to IC(50)s of 0.008 to 0.12 micro M for clavulanic acid. Against class C and class D enzymes, however, the activity of AM-112 was between 1,000- and 100,000-fold greater than that of clavulanic acid. AM-112 had affinity for the penicillin-binding proteins (PBPs) of Escherichia coli DC0, with PBP2 being inhibited by the lowest concentration of AM-112 tested, 0.1 micro g/ml. Ceftazidime was combined with AM-112 at 1:1 and 2:1 ratios in MIC determination studies against a panel of beta-lactamase-producing organisms. These studies demonstrated that AM-112 was effective at protecting ceftazidime against extended-spectrum beta-lactamase-producing strains and derepressed class C enzyme producers, reducing ceftazidime MICs by 16- and 2,048-fold. Similar results were obtained when AM-112 was combined with ceftriaxone, cefoperazone, or cefepime in a 1:2 ratio. Protection of ceftazidime with AM-112 was maintained against Enterobacter cloacae P99 and Klebsiella pneumoniae SHV-5 in a murine intraperitoneal sepsis model. The 50% effective dose of ceftazidime against E. cloacae P99 and K. pneumoniae SHV-5 was reduced from >100 and 160 mg/kg of body weight to 2 and 33.6 mg/kg, respectively, when it was combined with AM-112 at a 1:1 ratio. AM-112 demonstrates potential as a new beta-lactamase inhibitor.

Effective Treatment of Peritoneal Dialysis-Associated Peritonitis with Cefazolin and Ceftazidime in Children

To evaluate the use of the combination of cefazolin and ceftazidime for initial treatment of peritoneal dialysis (PD)-related peritonitis in pediatric patients. Retrospective nonrandomized study. Pediatric dialysis units of the University Medical Center of Utrecht and Nijmegen, The Netherlands. 40 children (median age 5.4 years) who were treated with PD during the study period of 4.5 years. All 50 episodes of peritonitis that occurred during the study period were evaluated by review of medical records. Patients were given intraperitoneal ceftazidime 500 mg/L dialysis fluid, and cefazolin 500 mg/L as a loading dose, followed by a maintenance dose of ceftazidime 125 mg/L and cefazolin 100 mg/L, intraperitoneally, 4 times daily. Antibiotics were continued for 14 days. After identification of the causative microorganism, one of the antibiotics was discontinued in 34 cases, and the antibiotic schedule was adapted in 2 cases. All cases were initially cured within 3 days. In 5 cases (10%), there was a peritonitis with the same organism recurring within 2 weeks after completion of treatment. There were 4 cases of PD-related peritonitis caused by pseudomonas, all of which were cured. The antibiotic combination of cefazolin and ceftazidime is effective for the initial therapy of PD-related peritonitis in children. The toxic complications of aminoglycosides are avoided with this combination.