Application of pharmacokinetic/pharmacodynamic analysis to evaluate the adequacy of antimicrobial therapy for pediatric acute otitis media in Spain before and after the introduction of the PCV7 vaccine.

OBJECTIVE: To evaluate, by applying pharmacokinetic/pharmacodynamic (PK/PD) analysis, if the change in antibiotic susceptibility after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in Spain had any influence on the usefulness of the antimicrobials more frequently used as empirical treatment of pediatric acute otitis media (AOM). METHODS: PK parameters and susceptibility of Streptococcus pneumoniae and Haemophilus influenzae were obtained from bibliography. Monte Carlo simulation was used to estimate the cumulative fraction of response (CFR), understood as the expected probability of therapy success. For amoxicillin and amoxicillin/clavulanate, the target was free antibiotic concentration remaining above the minimum inhibitory concentration (MIC) for ≥50% of the dosing interval (fT>MIC≥50%), whereas for cefuroxime axetil and cefotaxime, the target was fT>MIC≥60%. CFR values ≥90% were considered successful. RESULTS: When all serotypes of S. pneumoniae are considered, amoxicillin and cefotaxime turned out to reach a high probability of success, and difference before and after vaccination was scarce. For H. influenzae, CFR values were higher with amoxicillin/clavulanate than with amoxicillin. For both microorganisms, cefuroxime axetil resulted in low probability of success in the two periods of study. CONCLUSIONS: We have shown that the introduction of the PCV7 vaccination did not lead to changes in the probability of success of the current empiric treatments of the AOM. Integrated PK/PD analysis has demonstrated to be a useful tool to identify changes in antimicrobial activity after the implantation of a vaccination program, providing complementary information to the simple assessment of MIC values.

Population Pharmacokinetic Model-Based Evaluation of Standard Dosing Regimens for Cefuroxime Used in Coronary Artery Bypass Graft Surgery with Cardiopulmonary Bypass.

The purpose of this study was to investigate the population pharmacokinetics (PK) of cefuroxime in patients undergoing coronary artery bypass graft (CABG) surgery. In this observational pharmacokinetic study, multiple blood samples were collected over a 48-h interval of intravenous cefuroxime administration. The samples were analyzed by using a validated high-performance liquid chromatography (HPLC) method. Population pharmacokinetic models were developed using Monolix (version 4.4) software. Pharmacokinetic-pharmacodynamic (PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 468 blood samples from 78 patients were analyzed. The PK for cefuroxime were best described by a two-compartment model with between-subject variability on clearance, the volume of distribution of the central compartment, and the volume of distribution of the peripheral compartment. The clearance of cefuroxime was related to creatinine clearance (CLCR). Dosing simulations showed that standard dosing regimens of 1.5 g could achieve the PK-PD target of the percentage of the time that the free concentration is maintained above the MIC during a dosing interval (fTMIC) of 65% for an MIC of 8 mg/liter in patients with a CLCR of 30, 60, or 90 ml/min, whereas this dosing regimen failed to achieve the PK-PD target in patients with a CLCR of ≥125 ml/min. In conclusion, administration of standard doses of 1.5 g three times daily provided adequate antibiotic prophylaxis in patients undergoing CABG surgery. Lower doses failed to achieve the PK-PD target. Patients with high CLCR values required either higher doses or shorter intervals of cefuroxime dosing. On the other hand, lower doses (1 g three times daily) produced adequate target attainment for patients with low CLCR values (≤30 ml/min).

Iontophoresis of amoxicillin and cefuroxime: rapid therapeutic concentrations in skin.

CONTEXT: Amoxicillin (AMX) and cefuroxime (CFX) are antibiotics used often to treat skin bacterial infections. Typically, high oral doses are required to achieve minimum inhibitory concentration (MIC) at the site of infection that may affect only a very small area of skin. OBJECTIVES: To lower side effects and increase therapeutic effectiveness, the percutaneous absorption and retention of AMX and CFX administered by iontophoresis was investigated in a rabbit model by measuring dermis concentrations via microdialysis. METHODS: Iontophoresis was performed using a stainless steel electrode and a non-woven polypropylene pad. The cartridge pad was soaked with a solution of AMX in glycerin or of CFX in glycerin/water (60:40). Constant current density of 0, 100, 200 or 300 µA/cm(2) was applied for 60 min. RESULTS: For AMX, therapeutically effective skin concentrations were detected immediately after the application of electrical current for any of the current density tested and remained above it for at least 2 h from the end of iontophoresis. For CFX, skin concentrations rose above MIC only at the higher current densities and fell below the MIC by the end of the experiment. CONCLUSION: Iontophoresis is a promising method to obtain a fast and sustained concentration of AMX and CFX in skin.

Etiología y sensibilidad de los uropatógenos identificados en infecciones urinarias bajas no complicadas de la mujer (Estudio ARESC): implicaciones en la terapia empírica / Etiology and sensitivity of uropathogens identified in uncomplicated lower urinary tract infections in women (ARESC Study): implications on empiric therapy

Pacientes y método: Estudio multicéntrico ARESC de 9 hospitales españoles, que incluyó de forma consecutiva 803 mujeres, de edades entre 18 y 65 años, con cistitis no complicada, con el fin de identificar la etiología y evaluar su sensibilidad a 9 antimicrobianos. Resultados: De 803 pacientes consecutivas con ITU baja no complicada, fueron finalmente incluidas 784 pacientes. El urocultivo fue positivo en el 87,7% de las muestras. De un total de 650 uropatógenos, Escherichia coli (E. coli) fue el más frecuente (79,2%), seguido por Staphylococcus saprophyticus (4,4%), Proteus mirabilis (4,3%), Enterococcus faecalis (3,2%) y Klebsiella pneumoniae (2,3%). E. coli mostró una elevada sensibilidad a fosfomicina (97,2%), nitrofurantoína (94,1%) y algo menor a ciprofloxacino (88,1%). Las tasas de resistencia a fluorquinolonas fueron más elevadas en mujeres postmenopáusicas (17 frente a 10%). E. coli sigue presentando unas elevadas resistencias a ampicilina (65%) y a cotrimoxazol (34%), y en la actualidad, aproximadamente un 25% de las cepas son resistentes a amoxicilina/clavulánico y cefuroxima. Conclusiones: En España se observan elevados índices de resistencia de E. coli a antibióticos de amplio uso. Fosfomicina y nitrofurantoína preservan una elevada actividad in vitro. Considerando otros aspectos prácticos, como la posología (una sola dosis) y la influencia del consumo total de quinolonas sobre los niveles de resistencia en enterobacterias y en otros microorganismos, fosfomicina trometamol representa una alternativa empírica de primera elección para la cistitis no complicada de la mujer (AU)

Background and objective: To determine the etiology and susceptibility of uropathogens identified in women with uncomplicated lower urinary tract infections (UTI). Patients and methods: In a multicenter study (ARESC) in 9 Spanish hospitals, 803 female patients with uncomplicated cystitis were consecutively enrolled and evaluated to identify the uropathogens and their susceptibility to 9 antimicrobials.Results: Of 803 patients with uncomplicated cystitis, 784 patients were included. A positive urine culture was found in 87.7% of the samples. Of the 650 pathogens isolated, Escherichia coli (E. coli) was the most frequent (79.2%) followed by Staphylococcus saprophyticus (4.4%), Proteus mirabilis (4.3%), Enterococcus faecalis (3.2%) and Klebsiella pneumoniae (2.3%). E. coli showed a high rate of susceptibility to phosphomycin (97.2%), nitrofurantoin (94.1%) and somewhat lower to ciprofloxacin (88.1%). Fluorquinolone resistance rates were higher among postmenopausal women (17 versus 10%). E. coli was highly resistant to ampicillin (65%) and cotrimoxazole (34%) and 25% of the strains were resistant to amoxicillin/clavulanalic acid and cefuroxime. Conclusions: In Spain, E. coli shows high resistance rates to widely used antimicrobial antibiotics. Phosphomycin and nitrofurantoin have a high in vitro activity. Taking into account practical aspects such as convenience (only one dose), and the influence of the amount of fluorquinolone use on enterobacteriaceae and other microorganisms resistance levels, phosphomycin trometamol represents the option of first choice for the empirical treatment of uncomplicated cystitis in women (AU)

Pharmacokinetics of cefuroxime in traumatic wound secretion and antibacterial activity under vacuum therapy.

The objective of this study was to investigate the pharmacokinetics of cefuroxime in wound secretion and the antibacterial activity of the traumatic wound secretion in patients receiving cefuroxime and in those not receiving antibiotics. Included in the present controlled, prospective, non-randomized study were 12 patients with an open fracture who needed vacuum therapy (group A) and 12 patients with a closed fracture, who, due to soft tissue damage, also underwent treatment with vacuum therapy (group B). Wound secretion was obtained on the first, third and fifth postoperative days and exposed to the test bacteria, Staphylococcus aureus and Staphylococcus epidermidis. Patients in group A underwent systemic antibiotic treatment with cefuroxime administered intravenously at a dose of 1.5 g every 8 hours. Patients in group B did not receive antibiotics. Cefuroxime concentrations were determined using high-performance liquid chromatography (HPLC). Antibacterial activity was determined using the inhibition test. Maximum cefuroxime concentrations in wound secretion were measured at 4-5 hours following intravenous administration and, with a mean concentration of 10 mg/l, remained consistently above the minimum inhibitory concentration (MIC) for the test bacteria at all points during the measurement period. As expected, the antibacterial activity of the wound secretion in patients in group A (cefuroxime) was higher than that in group B (no antibiotics). In group A, antibacterial activity against S. aureus was 94.6% and 100% against S. epidermidis. In group B, antibacterial activity against S. aureus was 61% and 81% against S. epidermidis. Cefuroxime reaches the highest level in wound secretion after 4 hours. The high antibacterial activity of the wound secretion in traumatic closed fractures is elevated by cefuroxime. in addition, our findings show that vacuum therapy of wounds is suitable as a non-invasive method for studying the pharmacokinetics of antibiotics.

Quantification and prediction of skin pharmacokinetics of amoxicillin and cefuroxime.

The purpose of this project was to develop and validate a pharmacokinetic model and to quantify the rate and extent of distribution between plasma and skin of two beta-lactam antibiotics, amoxicillin (AMX) and cefuroxime (CFX), which are frequently administered systemically to treat skin and skin structure infections. Dosing regimens are usually based on plasma concentration, however, concentrations at the target site are better correlated with the effect. For each antibiotic, three different i.v. bolus doses were administered to three female rabbits according to a randomized cross-over design and plasma samples were collected serially. Skin concentrations were obtained by continuous microdialysis. Skin and unbound plasma concentrations were fitted simultaneously using a semi-physiological model and the transfer constants plasma/skin (K(in)) and skin/plasma (K(out)) were estimated. K(in) and K(out) were then used to predict skin concentrations from the plasma levels obtained from an oral administration of AMX or from an i.v. bolus of CFX. The predicted skin profiles were similar to those measured by microdialysis during the actual experiments. In conclusion, this study shows that it is possible to generate a reasonable prediction of skin pharmacokinetics from any plasma level once a careful characterization of the transfer process between plasma and skin has been made.

Estudo da disposição cinética da cefuroxima em pacientes submetidos à cirurgia de revascularização do miocárdio com circulação extracorpórea e hipotermia / Study of kinetic disposition of cefuroxime on patients submitted to cardiac surgery with extracorporea and hypothermia circulation

A circulação extracorpórea com hipotermia (CEC-H) é um procedimento comumente utilizado em cirurgias cardíacas, que representa um fator de risco para o paciente por promover extensa hemodiluição e profundas alterações fisiológicas. Nestas cirurgias, utiliza-se a cefuroxima com antimicrobiano para profilaxia de infecções, estando sua concentração inibitória mínima (CIM IND. 90) na faixa de 4 a 16g/mL dependendo da espécie e cepa bacteriana. Vários esquemas posológicos tem sido propostos para a profilaxia com este antimicrobiano. Assim, o objetivo do presente estudo foi investigar a farmacocinética e a disponibilidade sistêmica da cefuroxima, administrada I.V., bolus, na dose de 1,5g a 17 pacientes submetidos à cirurgia cardíaca com ou sem CEC-H...(AU)

Suitability of cefotiam and cefuroxime axetil for the perioperative short-term prophylaxis in tonsillectomy patients.

The efficacy of the perioperative short-term prophylaxis with cefotiam (CAS 66309-69-1) and cefuroxime axetil (CAS 64544-07-6) was analysed by the assessment of the pharmacological kinetics in the serum and the tonsil tissue in 50 patients with recurrent tonsillitis. Twenty-four patients received 1 g cefotiam by the intravenous route 30 min to 4 h before the tonsillectomy, and 26 patients received 250 mg cefuroxime axetil orally 1 to 6 h before the tonsillectomy. Bactericidal serum levels were reached for cefotiam up to 4 h after intravenous application and for cefuroxime axetil up to 3 h after oral application. In the tissue of the tonsil there were proved levels which were definitely above the MIC 90 (MIC = minimum inhibitory concentration) known for the clinically relevant germs for cefotiam after 30 min up to 2 h, for cefuroxime axetil after only 2 h. Considering the distribution areas, the capacity of the protein binding and the microbiological measuring methods, one can expect an efficient antibiotic coverage after an intravenous one-shot bolus injection of 1 g cefotiam from 30 min to 4 h and after oral application of 250 mg cefuroxime axetil on an empty stomach from 1 to 6 h. Because of the short duration of a tonsillectomy and the serum and tonsil tissue kinetics cefotiam and cefuroxime axetil are suitable for the perioperative antibiotic prophylaxis of high-risk patients.

Pharmacokinetics of antibiotic prophylaxis in major orthopedic surgery and blood-saving techniques.

The pharmacokinetics of cefuroxime, cefotiam, cefamandole, and ampicillin/sulbactam were randomly measured in 40 patients undergoing major orthopedic surgery associated with high blood and volume turnover and intraoperative blood salvage. Serum and bone concentrations and the pharmacokinetics occurring in the context of these procedures were measured. No changes in elimination half-life relative to a normal population occurred with cefuroxime, cefotiam, and ampicillin. Serum and tissue concentrations were slightly lower with cefamandole and sulbactam, but reapplication of the initial dose was required with all antibiotics 4 hours after the first application.

Antimicrobial treatment of an experimental otitis media caused by a beta-lactamase positive isolate of Haemophilus influenzae.

A gerbil model of otitis media induced by a beta-lactamase producing and non-serotypeable isolate of Haemophilus influenzae was used to assess the in-vivo efficacy of co-amoxiclav and cefuroxime at low (5 mg/kg) and high (20 mg/kg) doses. The MIC of the antibiotics tested against the pathogen was 1 mg/L (1/0.5 mg/L for co-amoxiclav). The organism was inoculated (+/-10(6) cfu) by transbullar challenge directly in the middle ear and antibiotic treatment was commenced 2 h post-inoculation and continued at 8 h intervals for three doses. Only high dose co-amoxiclav significantly reduced the number of culture-positive specimens as compared with untreated animals or with other treatment groups (91.7% as compared with 36.7% for high dose cefuroxime). The results obtained in any treatment group were related to middle ear antibiotic level/MIC. Antibiotic concentrations in the middle ear 90 min after administration were about 10% of serum levels at 15 min, probably related to a slight inflammatory response. Only after high dose co-amoxiclav did the concentration in the middle ear exceed the MIC by a factor of four. In otitis media with effusion, if indicated, antibiotics active in vitro should be administered in high doses and, to avoid side effects, probably in short courses.

Cefuroxime axetil. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy.

Cefuroxime axetil is an oral cephalosporin which is rapidly hydrolysed to the active parent compound, cefuroxime. Cefuroxime has a broad spectrum of in vitro antibacterial activity which encompasses methicillin-sensitive staphylococci and the common respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis and group A beta-haemolytic streptococci. Cefuroxime has broad spectrum activity against the beta-lactamase positive respiratory pathogens H. influenzae and M. catarrhalis; it is also active against penicillin-susceptible and -intermediate strains of S. pneumoniae. In clinical trials, cefuroxime axetil (administered twice daily) has been evaluated in the treatment of upper and lower respiratory tract infections and has demonstrated similar efficacy to established antibacterial agents, including amoxicillin/clavulanic acid and cefaclor. Five days' treatment with cefuroxime axetil was recently shown to be as effective as 10 days' treatment with either cefuroxime axetil or amoxicillin/clavulanic acid in patients with acute otitis media or acute bronchitis. Cefuroxime axetil was at least as effective as phenoxymethylpenicillin (penicillin V) in the treatment of patients with group A beta-haemolytic streptococcal tonsillopharyngitis. A number of studies have evaluated the efficacy of cefuroxime axetil as the oral component of intravenous to oral sequential therapy in hospitalised patients with lower respiratory tract infection. In each study patients received parenteral cefuroxime for approximately 2 days followed by cefuroxime axetil for 5 to 10 days. In comparative studies, cefuroxime sequential therapy was as effective as amoxicillin/ clavulanic acid sequential therapy and full courses of parenteral cefuroxime, cefotiam or cefoperazone. Adults with urinary tract infections and skin infections were also effectively treated with cefuroxime axetil, as were adults and adolescents with early stage lyme disease. Cefuroxime axetil is associated with a low incidence of adverse events, with gastrointestinal disturbances being the most frequently observed. Thus, cefuroxime axetil is an effective and convenient treatment for a wide range of infections and may be considered a therapeutic option when empirical treatment of community-acquired infections is required. Moreover, given the promising results of several intravenous/oral sequential treatment studies, cefuroxime axetil may also become established as an oral component of sequential treatment regimens.

Influence of hemodilution on cefuroxime levels and bacterial contamination of intra- and postoperative processed wound blood during hip replacement.

MATERIALS AND METHODS: In a prospective randomized study we investigated the effect of hemodilution on cefuroxime levels and bacterial contamination of processed shed blood during hip arthroplasty. 10 patients received cefuroxime 1,5 g as single shot prophylaxis before (group A), 10 after hemodilution (15 ml/KG) (group B). Cefuroxime levels in serum 1 h after administration, at the end of operation, after 12 h and in drainage-blood after 12 h were assessed by HPLC. Bacteriological study was performed from collecting bags (Vacufix), wound drainage blood and processed red blood cell concentrates, using pour plate technique and broth culture enrichment. RESULTS AND DISCUSSION: Mean concentrations of cefuroxime were higher in group B than group A, but differed not significantly. No bacterial contamination was found in collecting bags and wound drainages in both groups. Processed red cell concentrates in group B showed no growth. In group A, however, 3/10 were contaminated with < or = CFU/ml of coagulase-negative Staphylococcus, Staphylococcus epidermidis and Propionibacterium acnes. The differences between groups did not reach the level of statistical significance and could not be related to lower cefuroxime levels. No wound infection occurred in either group.

[The influence of selected antibiotics on the central action of aminophyllines--experimental studies]. / Wplyw wybranych antybiotyków na osrodkowe dzialanie aminofiliny--badania doswiadczalne.

Methylxanthines and some antibiotics can cause side effects, provoked by their central action, e.g. seizures. The epileptogenic effects of given drugs can be intensified during combined treatment, as a result of pharmacological interactions. In the present study the author investigated the influence of some commonly used antibiotics: benzylpenicillin, cefuroxime, doxycycline and amikacin upon central activity of methylxanthines in mice. The obtained results suggest, that all tested antibiotics, mainly benzylpenicillin, enhanced epileptogenicity of aminophylline in chemical seizures test. benzylpenicillin as only one among chosen antibiotics presented her own convulsant activity. During electrostimulation test, benzylpenicillin, doxycycline and amikacin intensified convulsions induced by methylxanthines. Only cefuroxime had no influence upon central action of methylxanthines in that experiments. Analysis of drugs' plasma levels, with using immunofluorescence methods, excluded pharmacokinetic interactions between them. Results of present investigation indicate, that there is a possibility of intensification of drugs' convulsant activity during combined treatment-aminophylline with some antibiotics in medical practice.

Cefuroxime versus cefazolin as prophylaxis in vascular surgery.

Although cefazolin prophylaxis has proven efficacy in vascular surgery, Staphylococcus aureus wound infections are still an important postoperative complication. In cardiac surgery, cefazolin's susceptibility to hydrolysis by staphylococcal beta-lactamase has been proposed to account for some prophylaxis failures. To determine whether the incidence of vascular wound infections can be reduced by administering a more beta-lactamase-stable cephalosporin, we undertook a prospective, randomized trial of cefuroxime versus cefazolin. Cefuroxime was administered as a 1.5 gm dose before operation and 750 mg every 3 hours during operation. Cefazolin was given as 1 gm before operation and 500 mg every 4 hours during operation. Both agents were continued every 6 hours after operation for 24 hours. Deep wound infections developed in seven of 272 (2.6%) cefuroxime and three of 287 (1.0%) cefazolin recipients (p = 0.2). Staphylococcus aureus wound infections occurred in five cefuroxime versus two cefazolin recipients. In vitro evaluation of six of the study isolates plus an additional eight S. aureus strains from vascular wound infections showed greater susceptibility of the strains to cefazolin than cefuroxime (median minimal inhibitory concentrations of 0.5 and 2.0 micrograms/ml, respectively, p less than 0.05). Furthermore, despite its more frequent intraoperative redosing, cefuroxime exhibited lower trough serum concentrations than cefazolin. Among cefuroxime recipients, infection-associated procedures were significantly longer than infection-free procedures (p less than 0.05), suggesting that low tissue antibiotic concentrations may have contributed to the pathogenesis of these infections. In contrast, the length of the procedure was not a risk factor for infection among cefazolin recipients.(ABSTRACT TRUNCATED AT 250 WORDS)