Intravenous amoxicillin-sulbactam against Escherichia coli: optimizing the dose, component ratio and infusion time using a human pharmacodynamic model.

Amoxicillin-sulbactam (AMX-SUL) is an aminopenicillin/beta-lactamase inhibitor combination currently available in 29 countries which may be a suitable option for treating intra-abdominal infections. the aim of this study was to identify the optimal dose and ratio between components of this formulation through an ex-vivo human pharmacodynamic model against Escherichia coli. Four volunteers were randomized to receive alternatively a single dose of AMX-SUL infused either over 30 min or 3h in the following ratios (g/g): 1/0.5; 1/1, 2/0.5 and 0/2. time-kill studies were performed with the 0-, 0.5-, 2-, 4-, 6- and 8-h post-dosing sera against E. coli ATCC 25922 (AMX MIC, 2 microg/ml; AMX-SUL MIC, 2 microg/ml) and E. coli ATCC 35218 (AMX MIC, 1024 microg/ml; AMX-SUL MIC, 4-8 microg/ml). AMX-SUL 1g/0.5 g infused over 30 min was only active at 0.5 h after dose, being inferior to both AMX-SUL 1g/1g and AMX-SUL 2g/0.5 g against E. coli ATCC 25922, for which the 2h post-dose serum proved active. When tested against E. coli ATCC 35218, AMX-SUL 1g/0.5 g and AMX-SUL 2g/0.5 g were active only at 0.5 h post-dose, whereas AMX-SUL 1g/1g showed bactericidal activity 0.5h post-dose and was able to inhibit bacterial growth 2 h post-dose. When infused over 3h, the antimicrobial activity of AMX-SUL was better than the 30-min infusion. Moreover, AMX-SUL 1g/1g was able to inhibit, and kill to some extent, the E. coli ATCC 25922 strain at 4h post-dose (i.e. 67% and 50% of a 6- and 8-h dosing interval, respectively). The present study suggests that 1g/1g is the best formulation for AMX-SUL against E. coli. The infusion over 3h optimizes its pharmacodynamic profile, as well as that of the 1g/0.5g combination. These findings encourage the performance of clinical trials to assess the efficacy of this combination, given as an extended infusion, in the treatment of community-acquired intra-abdominal infections.

Eficacia y tolerabilidad de esteroides epidurales vs. dosis bajas de esteroides mas metamizol mas D-propoxifeno administrados por vía paravertebral en pacientes con síndrome post-laminectomía / Efficacy and tolerability of epidural steroids vs low doses of steroids plus metamizol plus propoxyphene administered paravertebrally for postaminectomy syndrome patients

El reconocimiento de la acción antinociceptiva de los antiinflamatorios no esteroideos (AINEs) ha motivado su combinación con dosis moderadas de opiáceos con objeto de obtener una mayor analgesia, mientras que se reduce la necesidad de emplear dosis altas de esteroides. Un grupo de 142 pacientes adultos, que habían desarrollaron radiculopatía y lumbalgia después de la primera discectomia, en los que se demostró radiologicamente fibrosis y cicatriz periradicular, en el sitio de operación, se dividieron en dos subgrupos al azar. El grupo A (69 pacientes), fue tratado con inyecciones peridurales de 80 mg de metilprednisolona (MTP) en 3ml de bupivacaína 0.25% (BPV) después de obtener medidas controles de dolor, actividad física y la ingestión de medicamentos usando el Esquema del Progreso del Dolor, obteniendo un promedio control antes de iniciar el tratamiento. El grupo B (73 pacientes) fue tratado con inyecciones paravertebrales en los niveles L4-L5 y L5-S1, de 5 mg de metamizol (DPN), y 12.5 mg de propoxifeno (PPX) agregados a 10 mg de MTP y 1 ml de BPV 0.5%, bilateralmente en cuatro sesiones. Las mismas evaluaciones se llevaron a cabo cada 3 semanas después de cada tratamiento. Todos los pacientes mejoraron clínicamente, sin observarse diferencias significativas entre ambos grupos; Cuando se compararon los valores totales de mejoría clínica, se observaron los niveles controles significativos (p> 0.05) solo cuando se compararon con las mediciones de mejoría clínica, tomadas antes de iniciar el tratamiento en ambos grupos. Se presentaron efectos secundarios como incremento de peso, equimosis, edema fascies lunar y eritema facial en los pacientes del grupo A. La punción dural incidental (3) y cefalea por punción dural (2) se encontraron solo en el grupo A. Un paciente requirió ser tratado con un parche hematico epidural. Ocurrió parestesia en 1 paciente de cada grupo. No se encontraron diferencias significativas de mejoria entre grupos de pacientes con radiculopatia post-laminectomia lumbar, al ser tratados con MTP y BPV peridural y un grupo semejante que recibio la mitad de la dosis de MTP, mas BPV, DPN y PPX, en los espacios paravertebral L4-L5 y L5-S1. Los efectos secundarios y la morbilidad predominaron en el grupo tratado con inyecciones peridurales. Inyectando fuera del canal vertebral dosis reducidas de un opiáceo y de un antiinflamatorio, permitió usar solo la mitad de la dosis total de MTP. Ya que se obtiene una mejoría semejante, al evitar los efectos indeseables de los esteroides, así como las posibles complicaciones típicas de inyecciones epidurales, hacen de esta modalidad terapéutica una alternativa definitiva (AU)

As the clinical applications of the central antinociceptive action of the non-steroidal antiinflammatory agents have been recognized, their combination with mild doses of opiods has been explored in order to be able to reduce or eliminate the repetitious usage of steroids. A group of 152 adult patients with recurrent radiculopathy after the first laminectomy, at either L4-L5 or L5-S1 levels, in whom periradicular fibrosis and scarring had been shown at MRI exam, was separated at random into two subgroups. Subgroup A included 69 patients that were treated with four epidural injections of 80mg of methylprednisolone (MTP) in 3ml of 0.25% bupivacaine (BPV). Changes in pain level, physical activity and the type of medications used were followed using the Pain Progress Score that evaluates five parameters graded from 0 to 2, before initiating treatment and again before each of the three subsequent injections, given at three week intervals. Subgroup B included 73 patients treated by paravertebral injections of 40mg of MTP, 50mg of dipyrone (DPN), 12.5mg of propoxyphene (PPX) and 1ml of 0.5% BPV at the L4-L5 and L5-S1 spaces, bilateral. All patients improved clinically without observing statistically significant differences between the two groups; however, there was a significant difference (p< 0.05) when the post-treatment scores were compared to the control values, at every evaluation. There was however an important variant, as the patients in group A had more side effects (increased weight, edema, echymosis and moon fascies) and developed complications derived from the epidural injections (3 incidental dural punctures, two postdural puncture headaches, one of which required an epidural blood patch, as treatment). Similar clinical improvement was seen from either of the two treatment modalities studied; however, since most of the side effects and the morbidity typically observed after a series of epidural injections of steroids can be obviated by administering a reduced dose of steroids, an antiinflamatory agent and a low dose opiate in the paravertebral spaces adjacent to the previously operated level, this therapeutic alternative is recommended (AU)

Review of pharmacokinetic, pharmacodynamic and clinical studies with a modern combination of amoxicillin/sulbactam.

Amoxicillin/sulbactam is a modern antimicrobial combination. This combination proved to be useful for the treatment of several infections caused by different microorganisms, mainly with the beta-lactamase-producing species. In this review we present the most relevant pharmacokinetic, pharmacodynamic and clinical information associated with its use.

An ex-vivo pharmacodynamic study comparing bactericidal activity of amoxicillin/sulbactam, azithromycin, doxycycline and levofloxacin against Streptococcus pneumoniae.

We designed a 4-way crossover, ex-vivo pharmacodynamic study to compare the bactericidal rate of amoxicillin/sulbactam (AMX-SUL), azithromycin (AZM), doxycycline (DOX) and levofloxacin (LVX) against Streptococcus pneumoniae ATCC 49619. Six volunteers were randomized to receive alternatively a single tablet of the above drugs. Venous blood samples were obtained immediately before and at 2, 4 and 6 h after dose to perform time-kill studies and to determine antibiotic levels in serum. AMX-SUL was the only drug showing bactericidal activity with the sera obtained at every time after dose, as defined by a > or = 3-log10 cfu/ml decrease in the viable cell counts compared to the original inoculum after a 24-h incubation. AZM was only inhibitory at 2h after dose (i.e. a 1.3-log10 cfu/ml decrease in the viable cell counts) and proved bactericidal at 4 and 6 h post-dose. LVX proved bactericidal with the 2-h serum, was only inhibitory with the 4-h serum (e.g. a 1.5-log10 cfu/ml decrease) and was unable to avoid bacterial growth at 6 h post-dose. Bacterial growth was observed with DOX at every time after dose. This study may shed light on the understanding of breakthrough pneumococcal bacteremia during the course of oral therapy with AZM in patients with community-acquired nia (CAP), as well as the increasing treatment failures observed with LVX, and the selection of bacterial resistance during therapy reported with both drugs. It also provides the basis for a "warning signal" on the use of oral DOX and confirms the efficacy of AMX-SUL.

Efficacy of amoxicillin-sulbactam, given twice-a-day, for the treatment of community-acquired pneumonia: a clinical trial based on a pharmacodynamic model.

The present multicenter study reports the results of a clinical trial, designed on the basis of a pharmacodynamic study published previously (Bantar et al., J. Chemother 2000; 12: 223-227) to assess the efficacy of amoxicillin/sulbactam (875 mg/125 mg), given orally twice-a-day for 7 days in the treatment of patients with community-acquired pneumonia (CAP). Eighty-four evaluable subjects older than 19 years with clinical symptoms and features suggestive of CAP, consulting from June 2000 to March 2002 and meeting the PORT risk class I through III, were enrolled in the study. Mean age (y +/- standard deviation) was 46.7 +/- 16.3 and 62% of the patients had some co-morbidity predisposing for CAP. Several individuals (77.4%) fell into a low-risk class (i.e. PORT I or II) and 22.6% of patients belonged to a moderate-risk class at the start of treatment. Six patients (6.45%) had pneumococcal bacteremia. Streptococcus pneumoniae was the organism most frequently isolated (61.9% of all the patients in whom an etiologic diagnosis was made), followed by Haemophilus influenzae. Clinical success was observed in 97.6% of the patients (confidence interval 95%, 94.3%-100%). Almost all the individuals with clinical success became afebrile within the first 3 days of therapy. Ten patients (11.8%) reported mild or moderate adverse events (especially diarrhea) possibly related to the antimicrobial therapy, but this did not lead to withdrawal from the trial. The results of this study suggest that amoxicillin/sulbactam (875 mg/125 mg) is an efficacious and well tolerated option for treating patients with CAP belonging to a low-moderate risk class and support the use of a short, oral (7-day) b.i.d. regimen.

Rationale for treating community-acquired lower respiratory tract infections with amoxicillin/sulbactam combination through pharmacodynamic analysis in the setting of aminopenicillin-resistant organisms.

In order to establish a rationale for treating community-acquired lower respiratory tract infections, we assess here the pharmacodynamics of amoxicillin/sulbactam, 500mg/500mg, a formulation marketed in Argentina since 1988 and currently available in 17 countries, against the major pathogens, in comparison with that of a novel formulation (875mg/125mg, see J Chemother 2000; 12: 223-227). In time-kill studies, both bactericidal and inhibitory activity were seen in the 1.5- and 6-h sera, obtained from 12 volunteers after a single oral dose, against both a penicillin-susceptible and an -intermediate Streptococcus pneumoniae strain, as well as against Moraxella catarrhalis and a beta-lactamase-negative Haemophilus influenzae strain. Only the 1.5-h sera proved bactericidal against a penicillin-resistant S. pneumoniae strain (MIC, 2 microg/ml) and a beta-lactamse-positive H. influenzae isolate. This study suggests that amoxicillin/sulbactam (500mg/500mg) is still a suitable option for treating community-acquired lower respiratory tract infections, allowing a b.i.d. dosing schedule. Caution should be taken with pneumonia caused by beta-lactamase-positive H. influenzae or penicillin-resistant (MIC > or =2 microg/ml) S. pneumoniae isolates. Either shorter dosing intervals (t.i.d.) or a higher amoxicillin content in the formulation (i.e. 875 mg) may be required in these situations.

[Escherichia coli eradication from the blader urine by amoxicillin-sulbactam. Intrinsic activity of the inhibitor]. / Erradicación de Escherichia coli de la orina vesical por amoxicilina-sulbactam. Actividad intrínseca del inhibidor.

RATIONALE: At urine concentrations obtained after the oral administration of amoxicillin-sulbactam (500/500 mg) this combination inhibits roughly 90% of Escherichia coli and Proteus mirabilis strains. AIMS: To administer amoxicilin-sulbactam 875/125 mg and to determine: a) minimum inhibitory concentration (MIC) of sulbactam for E. coli and P. mirabilis; b) urine inhibitory titres power (UIT) against amoxicillin-resistant E. coli or P. mirabilis; c) urine concentrations of sulbactam; and to verify whether sulbactam 125 mg as single drug, attains a high enough UIT to support the intrinsic action of the inhibitor; and to compare the activity of amoxicillin-sulbactam and amoxicillin-clavulanate and that of sulbactam and clavulanate. METHODS: Twelve healthy volunteers received a single oral dose of amoxicillin-sulbactam 875/125 mg or amoxicillin-clavulanate 875/125 mg, according to a randomized cross-over design. Urine samples were drawn at: 0 (basal), 2, 4, and 6 hours after dosing. Urine pH, specific gravidity and UIP were assessed. Thirty nine strains isolated from urine samples were used: 30 TEM-1 producing E. coli strains and 3 extended spectrum CTX-M-2 betalactamase-producing E. coli; and 6 P. mirabilis resistant to both combinations. In 6 healthy volunteers, sulbactam 125 mg was administered orally and UIT against E. coli (MIC amoxicillin > 2048 mg/l) was assessed. RESULTS AND DISCUSSION: MIC-90 for amoxicillin plus sulbactam or clavulanate were similar to those for sulbactam or clavulanate alone, without any difference attributable to the chemical composition of the urine. The activity of amoxicillin plus the inhibitors could be due, not only to the inhibition of betalactamase but also to the intrinsic effect of the inhibitor. Both combinations showed an equivalent inhibitory activity. Two-hour UIT remained high for the entire 6-h evaluation period. Sulbactam concentration far exceed sulbactam MIC for the 6h-period, inhibiting urine E. coli. We disagree with the cut-off limit proposed for intermediate values of NCCLS, which, for these antimicrobial are 16/8, a value lower than those obtained in urine samples after the administration of betalactamase inhibitors. This may be an explanation for the beneficial effect of amoxicillin-sulbactam in the recovery of uncomplicated lower urinary tract infections in women when the involved strains were considered resistant by diffusional methods.

A pharmacodynamic model to support a 12-hour dosing interval for amoxicillin/sulbactam, a novel oral combination, in the treatment of community-acquired lower respiratory tract infections.

We evaluated, by time-kill studies, the pharmacodynamics of amoxicillin/sulbactam (AMX/SUL, 875 mg/125 mg), a novel oral combination, against the major respiratory pathogens in 12 volunteers receiving a single dose. The sera corresponding to 50% of a 12-h dosing interval displayed either bactericidal or inhibitory activity against both a penicillin-susceptible and a penicillin-intermediate Streptococcus pneumoniae strain (penicillin MIC of 0.03 and 0.25 microg/ml, respectively), as well as against a beta-lactamase-positive Moraxella catarrhalis and a beta-lactamase-negative Haemophilus influenzae strain. Both the peak samples and those corresponding to 4 h after dose (i.e. 33% of a 12-h dosing interval) proved active against both a penicillin-resistant S. pneumoniae (MIC, 2 microg/ml) and a beta-lactamase-positive H. influenzae strain. The AMX-SUL formulation evaluated in this study showed pharmacodynamic features that support clinical trials to assess its efficacy in the treatment of lower respiratory tract infections with a 12-h dosing interval regimen.

Pharmacokinetics and pharmacodynamics of amoxicillin-sulbactam, a novel aminopenicillin-beta-lactamase inhibitor combination, against Escherichia coli.

We evaluated the pharmacokinetics of amoxicillin-sulbactam (AMX-SUL), a novel drug combination, and its pharmacodynamics against Escherichia coli in 12 volunteers receiving a single oral dose (1, 000 mg). Peak serum bactericidal and urine inhibitory activities in most volunteers were observed against E. coli strains for which AMX-SUL MICs were low (2- to 4-mg/liter) (2 strains) and high (>/=16-mg/liter) (47 strains), respectively.

[The pharmacokinetic study of a daily dose of theophylline]. / Estudio farmacocinético de una dosis diaria de teofilina.

Theophylline pharmacokinetics, administered in tablets containing 600 mg in a sustained-release hydrophilic matrix for a once daily intake, was evaluated after being administered to 6 healthy volunteers during 7 days at 8 pm. Plasmatic levels at -2, 0, 2, 3, 4, 6, 8, 10, 12, 14, 18 and 24 hours in relation with 8 pm intake, were obtained at the 7th day of administration. A plasmatic curve was obtained with a maximum concentration at 12 hours of 10.18 mcg/ml, a minimum concentration of 3.27 mcg/ml and an area under the concentration/time curve of 198.4 mcg.h/ml. These data make it evident that the tablet studied shows a release profile without excessive peaks and an average concentration at steady state within therapeutical range, and suggests its use in asthma.

Estudio farmacocinético de una dosis diaria de teofilina. / [The pharmacokinetic study of a daily dose of theophylline]

Theophylline pharmacokinetics, administered in tablets containing 600 mg in a sustained-release hydrophilic matrix for a once daily intake, was evaluated after being administered to 6 healthy volunteers during 7 days at 8 pm. Plasmatic levels at -2, 0, 2, 3, 4, 6, 8, 10, 12, 14, 18 and 24 hours in relation with 8 pm intake, were obtained at the 7th day of administration. A plasmatic curve was obtained with a maximum concentration at 12 hours of 10.18 mcg/ml, a minimum concentration of 3.27 mcg/ml and an area under the concentration/time curve of 198.4 mcg.h/ml. These data make it evident that the tablet studied shows a release profile without excessive peaks and an average concentration at steady state within therapeutical range, and suggests its use in asthma.

Estudio farmacocinético de una dosis diaria de teofilina. / [The pharmacokinetic study of a daily dose of theophylline]

Theophylline pharmacokinetics, administered in tablets containing 600 mg in a sustained-release hydrophilic matrix for a once daily intake, was evaluated after being administered to 6 healthy volunteers during 7 days at 8 pm. Plasmatic levels at -2, 0, 2, 3, 4, 6, 8, 10, 12, 14, 18 and 24 hours in relation with 8 pm intake, were obtained at the 7th day of administration. A plasmatic curve was obtained with a maximum concentration at 12 hours of 10.18 mcg/ml, a minimum concentration of 3.27 mcg/ml and an area under the concentration/time curve of 198.4 mcg.h/ml. These data make it evident that the tablet studied shows a release profile without excessive peaks and an average concentration at steady state within therapeutical range, and suggests its use in asthma.

[Ambulatory ergometric and pressurometric results with a daily dose of 240 mg of diltiazem in labile hypertensive patients with threshold ergometry]. / Resultados ergométricos y presurométricos ambulatorios con 1 dosis diaria de 240 mg de diltiazem en hipertensos labiles con ergometría limítrofe.

The pharmacological treatment of hypertension raises not only the dilemma of the election of the most suitable drugs given to each patient, but also that of an effective control of the antihypertensive effect as well as undesirable reactions, including an accentuated hypotension. Continuous ambulatory monitoring (CAM) is an effective form of diagnosis and therapeutic control of hypertension. In order to evaluate the efficacy and tolerance of a new concentration of diltiazem (240 mg) in tablets of sustained release, for a single daily intake, a double blind, randomized, crossed study with placebo, was performed in 20 patients with mild to moderate hypertension and a positive ergometric test. Clinical, electrocardiographic, ergometric and CAM controls were carried out. A significant difference was observed for diltiazem monodosis 240 mg in relation to placebo with respect to the reduction of systolic and diastolic pressures, not only in clinical controls but also during the CAM, in both diurnal and nocturnal periods during 24 hours. In ergometric studies, a significant difference was also noted in the following parameters: total time of exercise, burden in kilos, systolic and diastolic blood pressure and the underlevel of ST. It is concluded that diltiazem monodosis, 240 mg, led to a sustained antihypertensive action throughout the 24 hours, with good clinical tolerance, improving ergometry and CAM. We suggest that diltiazem is a first choice drug for there patients in whom the exclusive treatment of hypertension has not prevented, up to now, the occurrence of ischemic cardiopathy.

Resultados ergometricos y presurometricos ambulatorios con 1 dosis diaria de 240 mg de diltiazem en hipertensos labiles con ergometria limitrofe / Ambulatory ergometric and pressurometric results with a daily dose of 240 mg of diltiazem in labile hypertensive patients with threshold ergometry

El monitoreo ambulatorio contínuo (MAC) constituye un eficiente elemento de diagnóstico y control terapéutico de la hipertensión arterial (HA). Con la finalidad de evaluar la eficacia y tolerancia de una nueva concentración de diltiazem (240 mg), en comprimidos de liberación programada para una toma diaria, se realizó un estudio doble ciego en 20 pacientes clínicos, electrocardiográficos, ergométricos y de MAC en los períodos basales, placebo y con droga activa. Se observó una diferencia significativa para diltiazem monodosis 240 mg en relación al placebo, en lo que se refiere al descenso de la presión arterial (PA) sistólica y diastólica, no sólo en los controles clínicos sino también durante el MAC tanto en el período diurno como en el nocturno. Esto ocurrió con el promedio de 24 horas y con el porcentaje de registros anormales. En los estudios ergométricos también se observó una diferencia estadísticamente significativa para diltiazem en los siguientes parámetros: tiempo total de la prueba, carga en Kilos, PA sistólica, y desnivel del ST. Se concluye que el diltiazem monodosis 240 mg fue capaz de mantener una eficaz acción antihipertensiva sostenida a lo largo de las 24 horas, con muy buena tolerancia clínica, induciendo una mejoría evidente en la ergtométría y en el MAC, lo que la hace una droga de primera elección en pacientes en los cuales el tratamiento exclusivo de la hipertensión arterial, hasta, ahora, no ha mejorado el pronóstico de la cardiopatia isquémica