ABSTRACT
BACKGROUND: The postantibiotic effect (PAE) of meropenem and ciprofloxacin was studied in the presence of the antineoplastic agent 5-fluorouracil (5-FU). The purpose of the study was to investigate whether the PAEs of the combinations differed from the PAEs of the antibiotics alone. METHODS: The PAEs of the combinations of 5-FU plus meropenem or ciprofloxacin were determined with viable counts against four reference strains of Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli and two clinical isolates of S. epidermidis. The results were compared with the PAEs of the antibiotics drugs and 5-FU alone. The gram-positive strains were tested for slime production, both alone and in the presence of 5-FU. RESULTS: Against two of the three tested strains of S. epidermidis, the combination of ciprofloxacin and 5-FU gave a synergistic prolongation of the PAE in comparison with the PAEs induced by the drugs alone. The combinations showed indifference against the other bacteria. The combination of meropenem and 5-FU had a synergistic PAE against one of the three tested strains of S. epidermidis and an additive effect against E. coli but showed indifference against the rest of the strains. CONCLUSIONS: The presence of 5-FU did not influence the PAEs of the antibiotics against most of the tested strains, but caused a synergistic prolongation of the PAEs induced by ciprofloxacin and meropenem against some of the tested strains of S. epidermidis. 5-FU inhibited slime production in the same S. epidermidis strains, which might have contributed to the longer PAE.
Subject(s)
Anti-Infective Agents/pharmacology , Antimetabolites, Antineoplastic/pharmacology , Ciprofloxacin/pharmacology , Fluorouracil/pharmacology , Thienamycins/pharmacology , Anti-Infective Agents/pharmacokinetics , Antimetabolites, Antineoplastic/pharmacokinetics , Ciprofloxacin/pharmacokinetics , Drug Interactions , Fluorouracil/pharmacokinetics , Meropenem , Microbial Sensitivity Tests , Staphylococcus epidermidis/drug effects , Staphylococcus epidermidis/physiology , Thienamycins/pharmacokineticsABSTRACT
BACKGROUND: The bactericidal effect of some antibiotic and antineoplastic agents commonly used in clinical practice was investigated to analyse whether the combinations act synergistically, have indifferent or antagonistic antibacterial effects compared to the effect of the antibiotics alone. METHODS: The rate of killing of meropenem, ceftazidime and tobramycin was studied against six different strains of Staphylococcus aureus and Escherichia coli, and the results were compared to the rate of killing of the antibiotics in combination with the cytostatic drugs doxorubicin, etoposide and 5-fluorouracil (5-FU). RESULTS: Tobramycin showed synergy against two strains of S. aureus after 3 h in the presence of 5-FU and against one strain of S. aureus in the presence of doxorubicin. Meropenem induced an antagonistic bactericidal effect against one isolate of S. aureus after 24 h. Ceftazidime expressed an indifferent bactericidal effect together with the cytostatic agents. The antineoplastic agents had no impact on the bacterial killing of any of the antibiotics against E. coli. CONCLUSIONS: Tobramycin expressed a significantly better bactericidal effect against S. aureus after 3 h in the presence of doxorubicin and 5-FU than tobramycin alone. Meropenem expressed antagonism against one clinical strain of S. aureus, but the cytostatic drugs did not affect the killing of other strains tested. Ceftazidime expressed indifferent bactericidal activity together with the antineoplastic agents.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/pharmacology , Ceftazidime/pharmacology , Cephalosporins/pharmacology , Doxorubicin/pharmacology , Escherichia coli Infections/drug therapy , Escherichia coli/drug effects , Etoposide/pharmacology , Fluorouracil/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Thienamycins/pharmacology , Tobramycin/pharmacology , Drug Interactions , Drug Therapy, Combination , Escherichia coli/pathogenicity , Meropenem , Microbial Sensitivity Tests , Staphylococcus aureus/pathogenicitySubject(s)
Ceftriaxone/therapeutic use , Cephalosporins/therapeutic use , Intestines/microbiology , Pneumonia/drug therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Ceftriaxone/administration & dosage , Cephalosporins/administration & dosage , Community-Acquired Infections/drug therapy , Drug Therapy, Combination , Feces/microbiology , Female , Hospitalization , Humans , Infusions, Intravenous , Male , Middle Aged , Treatment OutcomeABSTRACT
Eight patients with fever and neutropenia were given 2 g of ceftazidime i.v. as a bolus injection over the course of 3 min. The pharmacokinetic variables for ceftazidime were similar to those found previously in febrile, acutely ill, non-neutropenic patients. The area under the plasma-concentration-time curve was significantly smaller, and the terminal half-life (t1/2lambda(z)) significantly shorter, compared with elderly, healthy subjects (p < 0.005). Three patients survived long enough to be assayed after normalization of temperature and neutrophil counts. Glomerular filtration rates and clearances tended to be higher and the area under the curve and half-life lower on the day of fever and neutropenia. When considering our data in relation to known MIC values for common pathogens, ceftazidime administered intermittently every 6 h seems an appropriate regimen in patients with febrile neutropenia. Larger studies are needed to confirm this.
Subject(s)
Ceftazidime/pharmacokinetics , Cephalosporins/pharmacokinetics , Fever/metabolism , Neutropenia/metabolism , Adult , Aged , Area Under Curve , Ceftazidime/administration & dosage , Cephalosporins/administration & dosage , Female , Fever/etiology , Glomerular Filtration Rate , Half-Life , Humans , Injections, Intravenous , Leukemia/complications , Leukemia/metabolism , Male , Microbial Sensitivity Tests , Middle Aged , Neutropenia/etiologyABSTRACT
Twelve lymphoma patients received prophylaxis with co-trimoxazole during cytostatic treatment according to the MACOP-B regimen with cyclophosphamide, doxorubicin, vincristine, methotrexate, bleomycin, folinic acid and prednisone. Gastrointestinal mucosal damage from cytostatic treatment was estimated by WHO toxicity scores. No correlation was found between the degree of gastrointestinal damage and the presumed bioavailability of co-trimoxazole as estimated from serum levels of trimethoprim and sulphamethoxazole. The serum concentrations were above the minimum inhibitory concentration for Escherichia coli, Staphylococcus aureus and coagulase-negative staphylococci irrespective of the degree of toxicity. There is no apparent reason to change the dosing regimen of prophylactic co-trimoxazole when there is clinical evidence of damage to the gastrointestinal mucosa induced by chemotherapy.
Subject(s)
Anti-Infective Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Digestive System/drug effects , Trimethoprim, Sulfamethoxazole Drug Combination/pharmacokinetics , Adolescent , Adult , Biological Availability , Bleomycin/adverse effects , Cyclophosphamide/adverse effects , Digestive System/metabolism , Doxorubicin/adverse effects , Humans , Leucovorin/adverse effects , Lymphoma/drug therapy , Methotrexate/adverse effects , Middle Aged , Prednisone/adverse effects , Vincristine/adverse effectsABSTRACT
The method of microdialysis was used for collecting series of samples from the rabbit vitreous after systemic and intravitreous administration of ceftazidime. The purpose of the study was to compare the method with traditional pharmacokinetic sampling. Ceftazidime was injected intramuscularly (1 mg/kg) or intravitreally (1 mg) in rabbits, with a previously implanted microdialysis probe in the vitreous. The membrane was perfused with a buffer, and the dialysate was collected in samples where the concentration of the drug was analyzed by HPLC. After intramuscular administration, blood samples were taken to calculate systemic pharmacokinetics. The same procedures were repeated with rabbits with mild intraocular inflammation induced by the injection of 400 EU of endotoxin into the vitreous, 12-15 hr before drug administration. Pharmacokinetic parameters, such as half-life and AUC, were calculated. The penetration into the vitreous after intramuscular injection was higher (42%) in inflamed than in non-inflamed eyes (20%), suggesting an interference with the blood retinal barrier. Other kinetic parameters did not differ significantly between the groups. The advantage of the method is that fewer experimental animals can be used to obtain the necessary data compared to traditional pharmacokinetic methods. In conclusion, intraocular dialysis with chronically implanted probes is a technique well suited for pharmacokinetic studies of systemically administered ceftazidime or other drugs that will pass a dialysis membrane.
Subject(s)
Ceftazidime/pharmacokinetics , Inflammation/metabolism , Vitreous Body/metabolism , Administration, Topical , Animals , Ceftazidime/blood , Chromatography, High Pressure Liquid , Endotoxins , Female , Male , Microdialysis , RabbitsABSTRACT
The pharmacokinetics of meropenem were studied after single i.v. infusions of 15 mg meropenem/kg body weight in eight subjects with cystic fibrosis (CF) and eight healthy volunteers matched for age, sex, and weight. Significantly shorter terminal half-lives (mean, 0.74 h vs. 0.99 h) and mean residence times (mean, 1.09 h vs. 1.39 h) were noted in CF subjects. Plasma and renal clearances tended to be higher and distribution volumes smaller among the patients, but differences were not statistically significant. The results are consistent with the findings for many other beta-lactam agents used in CF patients. Assuming a MIC90 of 4 mg/l for meropenem against Pseudomonas aeruginosa, the time above the MIC was less than 3.3 h in six of the eight CF patients. This finding should be kept in mind when designing treatment regimens with meropenem in CF subjects.
Subject(s)
Cystic Fibrosis/complications , Pseudomonas Infections/complications , Pseudomonas Infections/drug therapy , Thienamycins/pharmacokinetics , Adult , Area Under Curve , Cystic Fibrosis/metabolism , Female , Humans , Male , Meropenem , Pseudomonas aeruginosa/drug effects , Thienamycins/therapeutic useABSTRACT
To determine the impact of neutropenia on the pharmacokinetics of meropenem, 14 patients with fever and neutropenia were given 1 g of meropenem i.v. every 8 h as an infusion over 30 min. The volume of distribution (16.2 l/1.73 m2) and the nonrenal clearance [75 ml/(min x 1.73 m2)] in this group were significantly increased compared to healthy subjects studied previously with identical techniques. The kinetic study was repeated when the patients had a normal temperature and a raised neutrophil count; most kinetic variables did not differ from the findings on the first day of treatment. The pharmacokinetic profile of meropenem in febrile neutropenic patients differs from earlier findings in healthy subjects. Considering these data and known minimum inhibitory concentration values for common pathogens, meropenem administered every 6 to 8 h seems an appropriate regimen in patients with febrile neutropenia. The shorter time interval may be used for treatment of Pseudomonas infection.
Subject(s)
Carbapenems/pharmacokinetics , Neutropenia/metabolism , Thienamycins/pharmacokinetics , Adult , Aged , Aged, 80 and over , Drug Administration Schedule , Female , Humans , Male , Meropenem , Middle Aged , Thienamycins/administration & dosageABSTRACT
Concentrations of doxycycline and penicillin G in serum and cerebrospinal fluid (CSF) were analyzed in 46 patients during treatment for neuroborreliosis. Twenty patients were treated intravenously with penicillin G at 3 g every 6 h (q6h), and 26 patients were treated orally with doxycycline at 200 mg q24h. All samples were collected on day 13 of treatment. The median concentrations of penicillin G in serum were 0.5, 37, and 5.6 micrograms/ml before and 1 and 3 h after drug administration, and that in CSF was 0.5 (range, 0.3 to 1.6) microgram/ml after 2 to 3 h. The median concentrations of doxycycline in serum were 2.1, 6.1, and 4.7 micrograms/ml before and 2 and 6 h after drug administration, and that in CSF was 0.6 (range, 0.4 to 2.5) microgram/ml after 4 h. All patients had concentrations of penicillin G or doxycycline in CSF above the lowest reported MICs of penicillin G (0.003 microgram/ml) and doxycycline (0.12 microgram/ml) for Borrelia burgdorferi. However, no patients had a drug concentration in CSF above the highest reported MIC of penicillin G (8 micrograms/ml), and only one had a drug concentration in CSF above the highest reported MIC of doxycycline (2 micrograms/ml), despite good clinical response to treatment. No treatment failure or relapse was observed during a 1-year follow-up, although one patient treated with penicillin G and one treated with doxycycline were retreated because of residual pain. The chosen dosages of penicillin G and doxycycline seem to give sufficient concentrations in serum and CSF for the treatment of neuroborreliosis.
Subject(s)
Borrelia burgdorferi Group , Doxycycline/therapeutic use , Lyme Disease/drug therapy , Penicillin G/therapeutic use , Adolescent , Adult , Aged , Blood-Brain Barrier/drug effects , Doxycycline/blood , Doxycycline/cerebrospinal fluid , Follow-Up Studies , Humans , Lyme Disease/blood , Lyme Disease/cerebrospinal fluid , Middle Aged , Penicillin G/blood , Penicillin G/cerebrospinal fluid , Treatment OutcomeABSTRACT
Amoxycillin and ofloxacin are both well absorbed after oral administration, despite being hydrophilic. We have studied the possibility of competition between these two drugs for a carrier-mediated transport system, since both drugs are absorbed by saturable processes in the rat small intestine. Oral doses of amoxycillin (3 g) and ofloxacin (400 mg) were given separately and in combination to six healthy volunteers. Blood samples were taken over 30 h and plasma concentrations of the respective drugs were measured by HPLC. Amoxycillin did not alter the pharmacokinetics of ofloxacin.
Subject(s)
Amoxicillin/pharmacology , Ofloxacin/pharmacokinetics , Adult , Chromatography, High Pressure Liquid , Double-Blind Method , Female , Humans , Intestinal Absorption/drug effects , MaleABSTRACT
In this study, the safety, tolerance, and pharmacokinetics of a single 1-g intravenous dose of cefepime (BMY-28142) were investigated. Twenty-three volunteers with various degrees of renal function were assigned to four trial groups according to glomerular filtration rates (GFR). Group IV consisted of five patients with end-stage renal disease undergoing treatment with hemodialysis. Cefepime concentrations in samples from plasma, urine, and infusion solutions were assayed with high-pressure liquid chromatography. The volume of distribution corresponded to the assumed extracellular fluid volume and did not differ significantly between the four groups. The area under the concentration-time curve increased as renal function decreased; in group II (GFR, 31 to 80 ml/[min x 1.73 m2]; n = 6), it was already three times higher than in group I (GFR, > or = 80 ml/[min x 1.73 m2]; n = 5). Mean residence time was 2.4, 6.8, 11.4, and 31.6 h for the four groups, respectively. Total clearance decreased (97.2, 34.6, 19.8, and 6.3 ml/[min x 1.73 m2]) with decreasing renal function, and a linear relationship between total plasma clearance and GFR was found with the regression equation y = 0.92x-2.0 (r = 0.991). Renal clearance was linearly correlated to GFR with the regression equation y = 0.87x-6.1 (r = 0.989), indicating that renal elimination is mainly by glomerular filtration. During hemodialysis, the extraction ratios were between 0.40 and 0.65. Dialysis clearance varied between 69.9 and 94.6 ml/(min x 1.73 m2).
Subject(s)
Cephalosporins/pharmacokinetics , Kidney Diseases/metabolism , Adult , Cefepime , Cephalosporins/administration & dosage , Cephalosporins/adverse effects , Female , Glomerular Filtration Rate , Humans , Infusions, Intravenous , Kidney Function Tests , Male , Pregnancy , Renal DialysisABSTRACT
The altered pharmacokinetic properties of, e.g., aminoglycosides in cystic fibrosis patients have to be considered when pulmonary exacerbations are treated. Since reported data on ciprofloxacin, a fluorinated quinolone, are conflicting, we compared intravenous and oral administration in cystic fibrosis patients when treating them for mild symptoms of pulmonary infection. All of the patients were colonized with Pseudomonas species. Ciprofloxacin was administered orally (15 mg/kg of body weight) or intravenously (6 mg/kg) twice a day for at least 10 days during separate treatment periods. Five healthy volunteers received single intravenous and oral doses. Pharmacokinetic evaluations were performed at first dose and at steady state. The results showed that cystic fibrosis patients have increased oral bioavailability of ciprofloxacin (80% in cystic fibrosis patients versus 57% in volunteers) and increased total clearance (688 ml/min in CF patients versus 528 ml/min in volunteers). Our data indicate that the pharmacokinetic properties of ciprofloxacin are altered in cystic fibrosis patients with mild symptoms of pulmonary exacerbations and that the changes most probably are due to cystic fibrosis per se or to the impact of chronic infection.
Subject(s)
Ciprofloxacin/pharmacokinetics , Cystic Fibrosis/metabolism , Administration, Oral , Adolescent , Adult , Biological Availability , Ciprofloxacin/administration & dosage , Ciprofloxacin/adverse effects , Cystic Fibrosis/microbiology , Drug Administration Schedule , Glomerular Filtration Rate/drug effects , Humans , Infusions, Intravenous , Lung Diseases/drug therapy , Lung Diseases/metabolism , Lung Diseases/microbiology , Male , Pseudomonas Infections/drug therapy , Pseudomonas Infections/metabolismABSTRACT
The pharmacokinetics of meropenem and its ring-opened metabolite (ICI 213,689) were investigated with eight young (20- to 34-year-old) and eight elderly (67- to 80-year-old) healthy male volunteers given single 30-min intravenous infusions of 500 mg of meropenem. All subjects had normal age-correlated glomerular function. The mean terminal half-life of meropenem was 1.27 h in the elderly subjects versus 0.81 h in the younger subjects (P less than 0.001). This and similar increases in mean residence time and area under the concentration-time curve were explained by a reduction in total [139 versus 203 ml/(min.1.73 m2); P less than 0.001], renal, and nonrenal clearances in subjects at advanced ages. The apparent volume of distribution and urinary recovery over 8 h were not significantly altered. With the metabolite, prolonged serum half-life and mean residence time, enlarged area under the concentration-time curve, and lower renal clearance but no significant changes in peak plasma concentration or urinary recovery were found in the elderly. The reduction in the renal excretion rate of meropenem and its metabolite corresponds to the age-associated physiological decline in renal function. The capacity to metabolize meropenem may also be slightly impaired in people at advanced ages. Dose reduction of meropenem should be considered for elderly patients.
Subject(s)
Aging/metabolism , Pyrroles/pharmacokinetics , Thienamycins/pharmacokinetics , Adult , Aged , Aged, 80 and over , Humans , Infusions, Intravenous , Male , Meropenem , Pyrroles/blood , Thienamycins/bloodABSTRACT
Five healthy volunteers and 18 patients with various degrees of renal impairment received 500 mg of meropenem intravenously as a 30-min infusion. Five dialysis patients were dosed 2 h prior to hemodialysis, and four of them were also dosed between hemodialysis treatments. Plasma and urine samples were collected for up to 48 h and 12 h, respectively. Concentrations of meropenem and its open ring metabolite ICI 213,689 were determined by high-performance liquid chromatography and radioimmunoassay, respectively. The subjects were divided into four groups with glomerular filtration rates (GFR) of greater than 80, 30 to 80, 5 to 29, or less than 5 ml/min. There were linear correlations between the GFR and the rates for total plasma clearance as well as renal clearance of meropenem (group mean values for total clearance of 186, 74, 53, and 19 ml/min/1.73 m2, respectively). In subjects with normal renal function, nonrenal clearance accounted for approximately 20% of total elimination, increasing to about 50% in patients with GFR between 5 and 29 ml/min/1.73 m2. The terminal half-life of meropenem increased from 0.9 h in the healthy volunteers to 6.8 h in patients with end-stage renal disease. The half-life of ICI 213,689 was 2.31 h in the healthy volunteers and increased to 23.6 h in patients with GFR of 5 to 29 ml/min. In patients with end-stage renal disease, half-lives could not be measured, as concentrations were hardly declining during the 48-h observation period. The area under the concentration-time curve for meropenem increased more than 10-fold. Both meropenem and its open ring metabolite were readily dialyzable, with dialysis clearances of 79 and 81 ml/min/1.73 m2, respectively.
Subject(s)
Kidney Diseases/metabolism , Thienamycins/pharmacokinetics , Adult , Aged , Chromatography, High Pressure Liquid , Female , Glomerular Filtration Rate/drug effects , Half-Life , Humans , Infusions, Intravenous , Male , Meropenem , Middle Aged , Renal Dialysis , Thienamycins/bloodABSTRACT
The efficacy and tolerance of roxithromycin 150 mg b.i.d. were compared with those of erythromycin stearate 500 mg b.i.d. in patients with lower respiratory tract infections. Out of 86 patients recruited for the study, 79 were evaluable for tolerance and 76 for efficacy. These patients were evenly distributed among the 3 investigational clinics, with 26, 25 and 28 patients, respectively. The diagnosis of lower respiratory tract infections was based on clinical, laboratory, radiological and/or physical findings and, when available, bacteriological and serological findings. The duration of treatment was 10 days, with follow-up at post-treatment visits directly after treatment and 6 weeks thereafter. The clinical outcome was satisfactory with no significant difference between the drugs. More patients reporting adverse events were on erythromycin than on roxithromycin (51.3% vs 17.5%; p = 0.003). The results suggest that roxithromycin is as effective as erythromycin stearate in the treatment of lower respiratory tract infections and causes fewer adverse effects.