Asunto(s)

RESUMEN

Ciprofloxacin plus azlocillin have been shown to exhibit in vitro synergy versus a variety of organisms, including Pseudomonas aeruginosa. This study examined this interaction in vivo, testing serum bactericidal activity (SBA) in six healthy male subjects after intravenous administration of ciprofloxacin 4 mg/kg (C), azlocillin 60 mg/kg (A), and the two simultaneously (C/A). Eight different organisms were tested: four isolates of P. aeruginosa with varying susceptibilities to C and A, and one isolate each of Escherichia coli (EC), Staphylococcus aureus (SA) Serratia marcescens (SM), and Klebsiella pneumoniae (KP), all of which were susceptible to both drugs. Blood samples were collected at the end of 30-min infusions and at 4 and 8 hr. Reciprocal titers were plotted versus time and area under the bactericidal titer curve (AUBC) calculated to assess antibacterial interactions. Results indicated that P. aeruginosa-1 (PA-1), EC, and KP were synergistically killed by C/A. AUBC for PA-1 were C = 36, A = 11, C/A = 144, p less than 0.05. AUBC for EC were C = 1059, A = 180, C/A = 1504, p = 0.05. AUBC for KP were C = 327, A = 97, C/A = 584, p = 005. Additive effects were demonstrated versus all of the other organisms except Serratia marcescens, where an indifferent effect was observed. Ciprofloxacin plus azlocillin may be a useful combination of the treatment of selected Gram-negative bacillary infections.

Asunto(s)

Asunto(s)

RESUMEN

Azlocillin plasma concentrations have been studied in 10 cystic fibrosis patients suffering from chronic pulmonary infections with Pseudomonas aeruginosa. Patients were given single i.v. doses of 100 e 200 mg/kg body weight as intravenous infusion over 30 minutes. Azlocillin plasma levels have been assayed by a rapid, sensitive and precise high performance liquid chromatographic method. After the dose of 100 mg/kg body weight concentrations of azlocillin decreased below the therapeutic concentrations after three hours; dose of 200 mg/kg was followed by plasma concentrations in the therapeutically desirable range during the 6-8 hours study period. The pharmacokinetic analysis offers further evidence of the dose-dependent nature of azlocillin elimination. Higher dosage of 200 mg/kg body weight and monitoring of plasma drug levels are recommended in the therapy of patients with cystic fibrosis.

Asunto(s)

RESUMEN

To compare the multiple-dose pharmacokinetics of two dosage regimens of azlocillin, we studied 12 healthy volunteers via a randomized, crossover design with a 2-week washout phase between regimens. Serum and urine samples were collected for 8 h following the fifth dose of a regimen of 4 g every 6 h and the fourth dose of a regimen of 5 g every 8 h. Data for concentrations in serum were fitted to a two-compartment open model by nonlinear regression. Statistically significant differences (P less than 0.05) were observed in the following parameters (mean +/- standard deviation) for the 4- and 5-g regimens, respectively: area under the serum concentration-time curve during the dosing interval, 592 +/- 140 versus 772 +/- 151 micrograms.h/ml; terminal elimination rate constant, 0.5364 +/- 0.0912 versus 0.4758 +/- 0.0486 h-1; renal clearance, 87.6 +/- 16.1 versus 76.1 +/- 13.5 ml/min; maximum drug concentration in serum, 381 +/- 89 versus 473 +/- 90 micrograms/ml; and minimum drug concentration in serum, 19 +/- 10 versus 8 +/- 4 micrograms/ml. No significant differences were seen in the following parameters: V1, V beta, k10, k12, k21, total systemic clearance, and nonrenal clearance. These data support the presence of saturable renal elimination of azlocillin, as well as the feasibility of an 8-h dosing interval.

Asunto(s)

RESUMEN

A granulocytopenic mouse model was used to elucidate the impact of dose spacing on the activity of netilmicin against Pseudomonas aeruginosa. A thigh infection was produced and then treated with netilmicin combined with azlocillin. Netilmicin was injected subcutaneously at decreasing doses every 20 min to result in plasma-concentration-time curves similar to those observed in patients on intravenous netilmicin treatment. A once-daily regimen was simulated and compared to a simulated conventional schedule of every 8 h. Identical total amounts of drug were used in both groups of comparatively treated mice. Therapeutic efficacy was quantitated by repeated determinations of surviving organisms in thigh homogenates. Combination therapy was significantly more effective than azlocillin treatment alone. In combination regimens the simulated once-daily netilmicin schedule killed the target organisms faster than the simulated thrice-daily regimen and was significantly more efficacious by 24 and 32 h in two out of three strains of Pseudomonas aeruginosa tested. It is concluded that the results of combination therapy of severe Pseudomonas aeruginosa infections in the immunocompromised host might be improved by choosing an aminoglycoside dosage interval of 24 h instead of the conventional 8 h.

Asunto(s)

RESUMEN

The efficacy of ciprofloxacin alone and in combination with azlocillin was compared with that of azlocillin plus tobramycin in a rat model of aortic valve endocarditis due to Pseudomonas aeruginosa. MICs against the infecting strain of ciprofloxacin, azlocillin and tobramycin were 0.125, 8, and 0.5 mg/l, respectively. Antimicrobials were administered 24 h after bacterial challenge and for six days. Mean peak/trough serum levels for ciprofloxacin (50 mg/kg i.v. q 12 h), azlocillin (500 mg/kg i.v. q 12 h) and tobramycin (6.5 mg/kg i.v. q 12 h) were: 10.5/0.2, 386/less than 16, and 6.2/less than 0.6 mg/l, respectively. Ciprofloxacin alone was more effective than the combination azlocillin-tobramycin in increasing survival (p less than 0.05), sterilizing blood (p less than 0.05) and valves (p less than 0.001), and in reducing bacterial titers in vegetations (p less than 0.001). Ciprofloxacin-azlocillin combination was not more effective than ciprofloxacin alone. Drug resistance was not encountered in post-treatment isolates with any therapy regimen.

Asunto(s)

RESUMEN

The concentration of azlocillin was determined using high performance liquid chromatography in serum and chondral tissue after intravenous infusion of azlocillin (75 mg/kg body weight). In serum the levels of ten patients (2 to 27 years of age, body weight 12 to 69 kg) decreased from 478 (30 min post infusion) to 120 micrograms/ml (120 min). In contrast, the concentrations in chondral tissue ranged between 24 and 35 mg/g tissue at the corresponding times. Although the mean levels suggest a remarkable penetration of azlocillin into chondral tissue, the high individual differences observed in the tissue levels (2.1 to 138 micrograms/g tissue) require a higher dosage to ensure sufficient antimicrobial therapy in all patients.

Asunto(s)

RESUMEN

The concentrations of azlocillin and mezlocillin in human prostatic tissue obtained by transurethral resection or enucleation were measured after two 2.0-gram doses of either drug. The average plasma concentration of azlocillin and mezlocillin at time of tissue sampling was 64.9 and 36.3 micrograms/ml, respectively, and tissue concentration at the time of sampling was 22.9 micrograms/g for azlocillin and 9.4 micrograms/g for mezlocillin. The plasma/tissue concentration ratio for mezlocillin was 0.25 and for azlocillin 0.35. Concentrations of mezlocillin in tissue obtained by transurethral resection were similar to those obtained by enucleation. Azlocillin and mezlocillin in appropriate doses achieve a concentration in human prostatic tissue above the inhibitory concentration for common bacterial pathogens.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

The pharmacokinetic characteristics of azlocillin were compared in 7 children with cystic fibrosis (CF) and 6 children without this disease who were all treated for infectious diseases. Azlocillin was administered as intravenous bolus injections in doses of 200 mg/kg. The serum concentrations were somewhat lower in CF than in non-CF as reflected by total areas under the serum concentration curves of 594 and 677 mg h/1, and serum levels after 8 hrs of 10.7 mg/1 in non-CF vs. a concentration below the detection limit in CF. The CF children had a lower serum half-life (1.1 hrs) than the children without this disease (3.3 hrs). The difference is explained by higher total body clearance in CF (12.7 1/h) than the non-CF group (8.4 1/h). The dose interval should either be shorter, or the doses increased, when azlocillin is administered to patients with CF.

Asunto(s)

RESUMEN

The pharmacokinetic profile of piperacillin and azlocillin after multiple-dose administration to healthy volunteers was studied. Twelve healthy volunteers received either piperacillin 4 g (as the sodium salt) or azlocillin 4 g (as the sodium salt) as a 20-minute infusion every six hours for five doses. After a one-week washout period, subjects received identical treatment with the alternate drug. Serum and urine concentrations of piperacillin and azlocillin were measured using a reversed-phase high-performance liquid chromatographic assay, and the pharmacokinetic analysis of serum concentration-versus-time data was performed using a computerized program. A standard open-model equation for i.v. infusions was used. Mean serum concentrations of piperacillin and azlocillin after dose 5 were 344 +/- 66 micrograms/mL and 414 +/- 86 micrograms/mL, respectively. The terminal elimination half-life of azlocillin (1.1 +/- 0.2 hr) was significantly longer than that of piperacillin (0.75 +/- 0.13 hr) (p less than 0.05). Total body clearance of azlocillin (125 +/- 25 mL/min) was significantly less than that of piperacillin (226 +/- 43 mL/min) after dose 5. Azlocillin showed accumulation between the first and fifth doses. Twelve hours after administration of dose 5, 75% of azlocillin and 57% of piperacillin were excreted unchanged into the urine. In healthy volunteers, azlocillin produced higher and more prolonged serum concentrations than piperacillin after administration of equivalent i.v. doses. Further studies are needed to determine the clinical importance of these observations.

Asunto(s)

RESUMEN

The efficacy of azlocillin, ticarcillin, and amikacin as single agents and the penicillin/amikacin combinations for treatment of Pseudomonas aeruginosa bacteremia during cyclophosphamide-induced severe neutropenia in a rat model were assessed. Equivalent antibiotic dosing was based on the time rat serum antibiotic levels were above the minimal bactericidal concentration for the challenge organism. Antibiotic therapy was administered for 62 hours after bacterial challenge. Antimicrobial efficacy was based on the rate of bacteremia, the emergence of resistant organisms during therapy, life-table survival analysis, and rat survival seventy-two hours after bacterial challenge. For infection with a P. aeruginosa strain susceptible to all study antibiotics, therapy with azlocillin and ticarcillin (given so as to be equipotent) were equivalent, as judged by bacteremia rates or rat survival. However, combination therapy prevented the emergence of organisms resistant to azlocillin, but not to ticarcillin. Amikacin-containing combinations were more effective than single-agent regimens.

Asunto(s)

RESUMEN

Left-sided endocarditis caused by Pseudomonas aeruginosa is frequently associated with failure of medical therapy in man. The efficacy of ciprofloxacin and netilmicin + azlocillin has been studied in 79 rabbits with aortic valve endocarditis caused by a serum-resistant strain of P. aeruginosa. Infected animals received either: no therapy; ciprofloxacin (80 mg/kg/day); or netilmicin (6.5 mg/kg/day) + azlocillin (400 mg/kg/day). Ciprofloxacin significantly lowered vegetation titers of P. aeruginosa at days 6 and 10 of therapy compared with netilmicin + azlocillin (P less than 0.001). Similarly, ciprofloxacin was significantly more effective in sterilizing vegetations (P less than 0.005), curing P. aeruginosa endocarditis (P less than 0.001), and preventing bacteriological relapse after discontinuing antibiotic therapy (P less than 0.005). Both antibiotic regimens were equally effective in sterilizing renal abscesses. Resistance to azlocillin was occasionally observed in vivo among P. aeruginosa isolates within cardiac vegetations during the second week of therapy, but not to ciprofloxacin or netilmicin.

Asunto(s)

RESUMEN

The single-dose pharmacokinetics of azlocillin and piperacillin were compared by using a randomized, crossover design. The concentrations of azlocillin in serum were consistently higher than those of piperacillin throughout an 8-h study. The area under the time-concentration curve of azlocillin was significantly greater than that of piperacillin, and the total body clearance of azlocillin was significantly lower than that of piperacillin.

Asunto(s)

RESUMEN

Azlocillin serum concentrations were followed in 9 severely ill patients with various degrees of renal dysfunction after single and repetitive dosage. All patients were treated concomitantly with a cephalosporin and/or an aminoglycoside antibiotic. Elimination halflives (t1/2 beta) were highly variable (62-1, 194 min), but no significant increase occurred in patients with stable renal function during repetitive dosage due to previously described nonlinear pharmacokinetic behavior of azlocillin. However, drug accumulation was observed in patients with deterioration of renal and hepatic function. The rise in drug accumulation can be disproportionally high if both routes of elimination are affected. In such cases, careful dosage adjustment of azlocillin is required to avoid toxic side effects.

Asunto(s)

RESUMEN

The efficacy of azlocillin + amikacin was compared to ciprofloxacin (with and without amikacin) in 96 rabbits with right-sided endocarditis due to Pseudomonas aeruginosa. Animals received either: no therapy (controls); amikacin (15 mg/kg/day) + azlocillin (400 mg/kg/day); ciprofloxacin (80 mg/kg/day) or amikacin + ciprofloxacin (above dosages). All three antibiotic regimens were significantly more effective than no therapy in reducing mortality (p less than 0.0005), preventing pulmonary infarction (p less than 0.0005) and reducing mean vegetation titers of P. aeruginosa (p less than 0.0005). Also, the three therapy regimens were equivalent in preventing bacteriologic relapse after discontinuing therapy. No development of antibiotic resistance in vivo was observed.

Asunto(s)

RESUMEN

The pharmacokinetics of high-dose azlocillin sodium was studied in 18 patients with cystic fibrosis. Nine male and nine female patients with a mean age of 14.7 years (range 3 to 29 years) participated in the study. They received azlocillin 450 mg/kg/day (as the sodium salt) in six divided doses. During a steady-state dosing interval, a dose of azlocillin was coadministered with a 10-mg/kg dose of iothalamate sodium as a 30-minute infusion. Serum concentrations of azlocillin and iothalamate were determined by high-pressure liquid chromatography assay. The data were analyzed using model-independent methods. The mean elimination rate constant for azlocillin was 0.64 +/- 0.22 hr-1 and the mean serum half-life was 1.22 +/- 0.39 hr. Total clearance of azlocillin, calculated by noncompartmental analysis, was 77.2 +/- 26.4 mL/min/sq m. Glomerular filtration rate, as estimated by measuring iothalamate clearance, was 79.6 +/- 21.9 mL/min/sq m. The total clearance of azlocillin correlated with iothalamate clearance. Patients with cystic fibrosis appear to eliminate azlocillin more rapidly than healthy individuals. This rapid elimination warrants the use of high doses to maintain high serum concentrations.

Asunto(s)

RESUMEN

We developed a rapid and precise high performance liquid chromatographic method (HPLC) for the determination of azlocillin and its metabolites penicilloate and penilloate in serum and tissue as well as in vivo as in vitro. The linear relationship (r greater than 0.99) of determination ranged between 0.05 and 10 micrograms. No interference with other serum components was observed. The metabolism of azlocillin in vitro was analysed in serum. Within 24 h the amount of penicilloate increased from 1.5% up to 18% and from penilloate up to 1% respectively. Buffer controls revealed a significant lower metabolism (4.7% penicilloate, 0.9% penilloate). These data suggest that the degradation of azlocillin does not only depend on bacterial beta-lactamase activity but is influenced by enzymatic activities within serum and human tissue.

Asunto(s)