Adequate Serum Levels Research Articles

Teicoplanin or vancomycin in the treatment of gram-positive infections?

The glycopeptide antibiotics vancomycin and teicoplanin have similar mechanisms of action on bacterial cell wall synthesis. Their spectra of activity are limited to Gram-positive bacteria, with the degree of bactericidal activity depending on the species of micro-organism. Staphylococcus aureus, Staphylococcus epidermis, enterococci and Clostridium difficile are generally sensitive, including methicillin-resistant strains of S. aureus and S. epidermidis. Glycopeptide resistance has recently emerged in staphylococci and enterococci. Vancomycin has a shorter half-life than teicoplanin and requires multiple dosing to maintain adequate serum levels. It can only be given by prolonged intravenous infusion over 1 h. In contrast, the pharmacokinetics of teicoplanin allow for once-daily dosing, either by rapid intravenous infusion or by the intramuscular route. The latter offers reliable absorption for patients with limited venous access and is also of benefit for out-patient therapy. Teicoplanin is a safer drug than vancomycin. It is associated with a lower incidence of nephrotoxicity or ototoxicity. Compared to vancomycin, the availability of the intramuscular route and the absence of a requirement for routine serum monitoring, together with the reduced need to treat drug-related side-effects make teicoplanin more cost-effective. It is as effective as vancomycin for most indications, is safe, easy to administer and an important agent for treating Gram-positive infections. Its role in hospitals is likely to increase if the price of drug acquisition is kept low.

To Use or Not to Use Cyclosporine-A: That is the Question

Crohn's disease is a chronic idiopathic, inflammatory disease of the bowel. Although the etiology is unknown, there has not been an infectious agent isolated and several studies (1,2) suggest that an activated immunological mechanism occurs in this disease. Recent findings (3,4) of an increased concentration of interleukin-1, interleukin-2, and soluble interleukin-2 receptors, as well as involvement of T cells in histologically examined tissue are further evidence that inflammatory bowel disease is immune mediated. Furthermore, the beneficial effect of steroids. 6-Mercaptopurine and methotrexate on active disease implicates the immune mechanism in the inflammatory response. Cyclosporine (CSA), a rapidly acting and potent immunosuppressive, has multiple effects on the immune system. CSA has been studied extensively in Crohn's disease; however, the results of these studies are conflicting because (a) CSA was given in different dosages, (b) CSA was given enterally rather than parenterally, and the endpoints differed in each study, contributing to the divergent results (5). Our successful experience at Mount Sinai Hospital may reflect the fact that all of our patients received intravenous CSA before starting oral medication. CSA absorption from the small bowel is a function of contact time that varies with smallbowel length (6), motility, and mucosal absorption. It is clear from the transplant experience that short bowel syndrome, graft-versus-host disease, and radiation enteritis will interfere with absorption of CSA. In children, in whom the small bowel is shorter than in adults, several studies have proven that adequate serum levels of CSA are difficult to attain (7). However, when given by continuous intravenous infusion, a steady therapeutic blood level is maintained. Our pharmacokinetic data clearly illustrate that when CSA is given orally, blood levels are erratic and subtherapeutic levels correlate with clinical activity.

The use of GnRH analogs for induction of the preovulatory gonadotropin surge in assisted reproduction and prevention of the ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) remains a potential severe complication of the use of gonadotropin therapy in ovulation induction and assisted reproduction technologies. In 1988, we reported preliminary results which demonstrated the ability of gonadotropin-releasing hormone analogs (GnRH-a) to trigger ovulation, and to prevent subsequent OHSS. In this report, we summarize our experience of 73 treatment cycles involving 44 high responders (i.e. patients with a previous history of severe OHSS, or with high estradiol levels (> 13 200 pmol/l) on the day of triggering the luteinizing hormone (LH) surge).In spite of the high estradiol levels (mean 24 202 pmol/l) and the large number of oocytes (mean 32.4), none of our patients developed severe OHSS. Luteal support with progesterone and estradiol valerate was necessary to maintain adequate serum levels of these hormones. Without such support, a precipitous decline in levels of estradiol and progesterone was observed. We believe that the use of GnRH-a i...

The use of vaginal tablets as a vehicle for steroid replacement in a donor oocyte program

Nine women enrolled in the donor egg program received in a preparatory cycle 6 mg of E2 by vaginal tablets two times per day for the first 14 days, followed by a combined preparation of 6 mg of E2 and 50 mg of P as vaginal tablets, two times per day for another 14 days. Adequate serum levels of E2 and P and favorable sonographic endometrial thickness were achieved throughout the cycle in all patients. Eight endometrial biopsies taken on days 25 to 26 were independently assessed as being representative of day 25 +/- 2. One endometrial biopsy was out of phase. It is concluded that vaginal tablets of E2, followed by a combined preparation of vaginal tablets of E2 and P, is an effective method for establishing an appropriately developed endometrium in a donor oocyte program. Endometrial preparation in donor oocyte programs can be simplified by the use of these tablets.

10 AMOXICILLIN PHARMACOKINETICS IN THE PRETERM INFANT

Amoxicillin (AM) is one of the most frequently used antibiotics in the treatment of bacterial infections in the preterm infants. Despite the widespread use of AM in neonatal intensive care units, pharmacokinetic studies in preterm infants are not available. The recommended dosage of AM is 50-100mg/kg/24h. We studied the multiple-dose pharmacokinetics of AM (25 mg/kg q12h) in 17 preterm infants (gest. age 29 ± 1.9 wks) on day 3 of life. Blood samples were taken before (t = 0) and 1/2, 1, 2, 4, 8, and 12 hrs after the AM dose and analyzed by HPLC-assay.The glomerular filtration rate (GFR) of all infants was simultaneously studied by means of the 24h continuous inulin infusion technique to investigate the effect of GFR on the clearance of AM. The results were:Conclusions. 1. Amoxicillin 25 mg/kg q12h results in adequate serum levels of AM in preterm infants with a gestational age below 32 weeks on day 3 of life. 2. The total body clearance of AM (1.0 ± 0.4 ml/min) and the GFR (1.0 ± 0.3 ml/min) are equal, indicating that AM is primarily excreted by glomerular filtration in the preterm infant.

Use of the hypoxic cell sensitizer etanidazole (SR-2508) with intravenous melphalan and prednisone in the treatment of multiple myeloma: A pharmacokinetic study

Purpose : A study was undertaken adding the alkylating agent sensitizer etanidazole to intravenous melphalan and oral prednisone for patients with multiple myeloma. This study explored the toxicity profile of these agents when given together and assessed the ability to attain adequate serum levels of etanidazole to permit sensitization to occur. Methods and Materials : Etanidazole was administered intravenously in two doses of 3 g/m 2 and 5 g/m 2 90 min apart immediately prior to the administration of intravenous melphalan and oral prednisone for three consecutive cycles (total dose 24 g/m 2). Patients received three additional cycles without etanidazole, allowing a comparison of hematologic toxicity from melphalan with and without etanidazole. Results : Hematologic toxicity was moderate (Grade 3 or 4), but severity was similar during cycles with and without etanidazole. Only one etanidazole. Only one patient developed a Grade 1 peripheral neuropathy questionably related to etanidazole. Most patients had etanidazole levels of ≥ 70 ug/ml for 7 h, a level felt to be necessary for sensitization to occur. Conclusion : Etanidazole, administered as described, results in adequate serum levels for potential alkylating agent sensitization, without significant toxicity.

Phase I pharmacokinetic study of the hypoxic cell sensitizer etanidazole with carboplatin and cyclophosphamide in the treatment of advanced ovarian cancer

Purpose : A Phase I study was undertaken to determine the maximum tolerated dose of the hypoxic cell sensitizer etanidazole which could be administered with carboplatin and cyclophosphamide, to determine whether adequate serum levels of etanidazole were achieved to allow for alkylating agent sensitization, and whether pretreatment with etanidazole altered carboplatin pharmacokinetics. Methods and Materials Patients received 2 g/m 2 of intravenous etanidazole followed by a second dose of 4 g/m 2 90 min later, followed by intravenous carboplatin (300 mg/m 2) and cyclophosphamide (600 mg/m 2) for four treatment cycles. Patients received an additional two cycles of carboplatin and cyclophosphamide without etanidazole. Results : Two patients who received a total of 24 g/m 2 of etanidazole developed Grade 1 neurotoxicity, and therefore etanidazole doses were not escalated further. The grade of granulocytopenia was worse after cycles with etanidazole than after those without ( p = 0.03), but clinical outcome was not different. Etanidazole levels were adequate for alkylating agent sensitization (> 70 ug/ml) in all patients for the majority of the 7 h of testing. Pharmacokinetic data suggested t 1 2α and t 1 2β for carboplatin were prolonged after pretreatment with etanidazole. Conclusion : Etanidazole, 2 g/m 2 followed by 4 g/m 2 90 min later, is safe and results in adequate serum levels for alkylating agent sensitization. Neurotoxicity appears to prevent dose escalation of etanidazole, and an interaction between etanidazole and carboplatin may have enhanced neurotoxicity in these patients.

Tricyclic dose requirements across pregnancy

In a series of eight pregnant women, the authors found that the doses of tricyclic antidepressants required to achieve remission of symptoms and adequate serum levels increased during the second half of pregnancy. During the final trimester, the mean dose required was 1.6 times the mean dose required when the patients were not pregnant.

A PHASE I TRIAL OF IMMUNOSUPPRESSION WITH ANTIIC AM-1 (CD54) mAb IN RENAL ALLOGRAFT RECIPIENTS

Several adhesion molecules contribute to the interaction between T cells and antigen presenting cells or target cells. Leukocyte function-associated molecule-1 (LFA-1[CD11a/CD18]) and intercellular adhesion molecule-1 (ICAM-1 [CD54]) are one such critical adhesive receptor-counter-receptor combination. The importance of ICAM-1 dependent adhesion in the rejection response was initially demonstrated in cynomolgus renal allograft recipients treated with the anti-ICAM-1 murine monoclonal antibody BIRR1. BIRR1 also appeared to limit ischemic damage in these animals. A Phase I clinical trial has subsequently been completed in 18 patients who received cadaver donor renal allografts at high risk for delayed graft function (prolonged preservation time, highly-sensitized recipient). An adequate BIRR1 serum level was associated with significantly less delayed graft function (P < .01) and rejection (P < .01). In 1-hr biopsies, mouse IgG was detected along the endothelium of the vessels and glomeruli in the graft. There were no instances of primary non-function (PNF), and current allograft survival (followup: 16-30 months) in these "high-risk" mAb-treated patients is 78%. There were 3 instances of PNF and a graft survival rate of 56% in the recipients of the contralateral kidney allografts treated with conventional immunosuppression. No significant "first-dose" effect was associated with BIRR1 administration. These results establish a dosing schedule and the clinical safety of BIRR1. They also suggest that inhibition of leukocyte adhesion by mAb therapy may be useful in controlling allograft rejection and possibly in limiting reperfusion injury. Thus, these observations support the clinical importance of accessory molecules in T cell function. We hypothesize that anti-CD54 mAb acts by blocking leukocyte adhesion to the endothelium, thereby interfering with sensitization or target cell interaction.

Vitamin A Status of Children in the Urban Slums of Karachi, Pakistan, Assessed by Clinical, Dietary, and Biochemical Methods

We assessed the vitamin A status of 532 children with an age range of 6-60 months who were living in slum areas of Karachi, Pakistan, using three methodologies: clinical eye examination, dietary vitamin A intake, and serum retinol level. No definite clinical signs of xerophthalmia were observed in any of these children. The mean +/- SD vitamin A intake estimated from a food frequency questionnaire for the group with inadequate (low and deficient) serum retinol levels (< 20 micrograms/dl) was 362 +/- 332 retinol equivalents (RE) compared with 431 +/- 332) RE in the group with adequate serum levels (P < 0.005). Deficient serum retinol levels (< 10 micrograms/dl) were present in 12 children (2%); two of these had a healed corneal scar. Low serum retinol levels (10-19 micrograms/dl) were present in 46%, while 51% children had adequate levels (> or = 20 micrograms/dl). The mean +/- SD serum retinol level for the inadequate (< 20 micrograms/dl) and adequate groups were 15.3 +/- 2.8 and 26.6 +/- 6.7 micrograms/dl, respectively. These results suggest that a significant number of children in these communities have low vitamin A levels and thus may constitute an at risk group. These results also suggest that the dietary intake method may be a simple and inexpensive screening tool for assessment of vitamin A status in communities.

Intensive care management of community-acquired Klebsiella pneumoniae

The clinical features of 18 patients with Klebsiella pneumoniae requiring intensive care unit (ICU) management are presented. All patients required ventilatory support; 17 were given constant positive pressure ventilation and 10 required greater than 10 cm positive end expiratory pressure. The clinical picture was characteristic: pre-existing medical disease, clinical features of severe pneumonia and copious purulent bronchial secretions, Gram--ve organisms on Gram's stain and lobar consolidation on the chest radiograph were common. Septicaemic shock, confusion and uncompensated metabolic acidosis were the presenting clinical features predicting a poor outcome. Antimicrobial chemotherapy, that combined an aminoglycoside and a third generation cephalosporin to ensure adequate early antibiotic serum levels, may help to improve the prognosis.

Parenteral Antibiotic Therapy in Outpatients: Quality Assurance and Other Issues in a Protohospital

Antibiotics can be administered parenterally to outpatients in order to achieve adequate serum levels to treat such infections as endocarditis, osteomyelitis and diabetic foot infections, and to eradicate such difficult-to-treat organisms as methicillin-resistant Staphylococcus aureus, cephalothin-resistant gram-negative bacilli and invasive fungal infections. At Intracare, a free-standing clinic for such therapy, 3,247 outpatients have been treated to date. Besides the type of infection, criteria for patient selection include improvement in the patient's condition, a desire to leave the hospital, an adequate support structure at home, patient compliance and adequate insurance coverage. The most frequently treated infections have been osteomyelitis, followed by infection of skin and skin structure. Ceftriaxone and cefazolin are the two most frequently utilized antibiotics. The program at Intracare is used to examine such issues of quality assurance as patient compliance, therapeutic outcome, adverse events and patient satisfaction in this largely unregulated multibillion dollar industry. It is likely that such infusion centers will evolve into protohospitals, day care centers for present-day medical-surgical patients not occupying intensive care beds.

Ornidazole achieves adequate serum levels during colorectal surgery and tissue penetration is high

Ornidazole achieves adequate serum levels during colorectal surgery and tissue penetration is high

Human Immunoglobulins for Intravenous Use: Comparison of Available Preparations for Group B Streptococcal Antibody Levels, Opsonic Activity, and Efficacy in Animal Models

Currently available human immunoglobulin preparations for intravenous use (IVIGs) are being used (with antibiotics) by some physicians for therapy of sepsis in newborns. Most neonatal sepsis and/or meningitis in this country is caused by group B Streptococcus (GBS), and most of these cases are due to type III GBS (III-GBS). The killing of III-GBS in vitro is dependent on specific IgG antibody. Adequate serum levels of specific III-GBS antibody protect the exposed newborn from the development of invasive disease. Therefore, III-GBS was used as a model to evaluate the activity of three IVIG preparations available for clinical use. Specific antibody levels, in vitro opsonophagocytic killing, and protective efficacy in animal models revealed differences in activity for III-GBS between the three IVIG preparations as well as between IVIG lots from the same manufacturer. Furthermore, it was found that the effect of IVIG using one of the assay methods may not reliably predict activity obtained using the other assays. These data document the inability to predict functional activity against a specific pathogen such as GBS on the part of a lot of IVIG chosen at random. In view of these findings and of the limited data evaluating clinical efficacy, IVIG cannot be recommended at this time for use in the therapy of infectious diseases such as neonatal sepsis.

Vancomycin during pregnancy: Does it cause hearing loss or nephrotoxicity in the infant?

Vancomycin was administered intravenously to 10 pregnant women for the treatment of methicillin-resistant Staphylococcus aureus infections. Auditory brainstem response testing and renal function studies were performed on the 10 babies in the experimental group and 10 babies in each of two control groups to determine the safety of vancomycin use during pregnancy. Auditory brainstem responses were not normal at birth in six infants from the three different groups studied ( N = 30) but were normal at 3 months in five. The sixth infant had conductive hearing loss unrelated to vancomycin use that spontaneously disappeared at 12 months of age. Renal function was normal in all infants. Vancomycin was detected in cord blood in two patients and in breast milk in one. Adequate serum levels were achieved with routine doses in eight mothers tested; no adverse reactions occurred. It appears that vancomydn use during the second and third trimesters of pregnancy does not produce sensorineural hearing loss or nephrotoxicity in the infant.

Oxacillin and tobramycin serum levels during cardiopulmonary bypass

Antibiotic prophylaxis in cardiac surgery is recommended to combat acquired infections caused by staphylococci and gram-negative bacilli. Prophylaxis seems effective provided blood levels are greater than minimal inhibitory concentrations (MIC). In this study, two doses of antibiotics were compared in 45 patients with normal renal function during cardiopulmonary bypass (CPB). All patients received 50 mg/kg of oxacillin. Group 1 (30 patients) also received 1 mg/kg of tobramycin, while group 2 (15 patients) received 2 mg/kg of tobramycin. Blood samples were taken after the administration of antibiotics, as well as at the onset and conclusion of CPB. Additional samples were taken before and after heparin injection before CPB, and from the arterial and venous cannulae of the bubble oxygenator during CPB. In both groups, oxacillin serum levels were constantly greater than MIC for susceptible bacteria. In group 1, tobramycin levels less than 2 micrograms/mL (MIC for most susceptible bacteria) occurred in four patients before CPB, in 14 patients at the onset of CPB, and in 19 patients at the conclusion of CPB. These low levels were not explained by heparin administration or absorption onto the CPB circuit, but were the result of hemodilution. In group 2, in which all the tobramycin levels were higher than 2 micrograms/mL, serum levels decreased from 9.9 +/- 3.4 (mean +/- SD) to 3.7 +/- 0.7 micrograms/mL throughout the procedure. Plasma creatinine did not change significantly in either group. It is concluded that in patients with normal renal function, doses as high as 50 mg/kg of oxacillin and 2 mg/kg of tobramycin may be necessary before CPB to provide adequate serum levels throughout CPB.

Cefoperazone in the treatment of peritonitis in continuous ambulatory peritoneal dialysis patients.

Cefoperazone is a third-generation cephalosporin that is active against a broad spectrum of gram-positive and gram-negative bacteria. We added this antibiotic to peritoneal dialysis solution at a concentration of 62.5 mg/L to treat peritonitis in six continuous ambulatory peritoneal dialysis (CAPD) patients. Serum drug concentrations were obtained at 0, 0.5, 1, 2, 4, and 24 h after instituting antibiotic therapy. Rapid uptake by blood of the antibiotic across the peritoneal membrane occurred when the latter was inflamed. Adequate bactericidal serum levels for many bacteria were obtained in less than 4 h. Cefoperazone effectively eradicated peritonitis in all patients.

Cefamandole pharmacokinetics during standard and pulsatile cardiopulmonary bypass.

The pharmacokinetics of cefamandole during standard or pulsatile cardiopulmonary bypass were studied in 13 adult cardiac surgery patients. All patients received 20 mg/kg of cefamandole intravenously at midnight before surgery, 6 AM on the morning of surgery and just prior to the initiation of cardiopulmonary bypass (CPB) surgery. Serum, skeletal muscle, and fat samples were taken at the beginning of CPB and at 30-minute intervals thereafter and assayed for cefamandole concentration. The average elimination rate constant and elimination half-life for cefamandole in patients undergoing standard CPB were 0.73 +/- 0.09 hour-1 and 0.94 +/- 0.11 hour, respectively. In contrast patients undergoing pulsatile CPB had significantly slower elimination rate constants (0.50 +/- 0.1 hour-1 and 1.4 +/- 0.28 hours, respectively; P less than or equal to .05). Area under the curve (AUC) values for cefamandole in fat and muscle tissue were higher in patients undergoing pulsatile CPB, but the differences were not statistically significant. Prolonged elimination from the serum, skeletal muscle, and adipose tissue, as compared with normal subjects, is seen with both pulsatile and standard CPB but is greater for the pulsatile method. Intraoperative dosing of cefamandole is required to maintain adequate serum and tissue levels for operations lasting longer than 4 or 6 hours in which standard or pulsatile CPB, respectively, are used.

The pharmacokinetics of medroxyprogesterone acetate following two different loading dose schedules in advanced carcinoma of the breast.

A loading dose of MPA employing a regimen of 1,000 mg six hourly for 8 doses can achieve plateau levels above 100 ng ml-1 within the first 36 h of treatment, without any untoward toxicity. This raises the possibility of shortening the time to response for this agent. The additional factor of the time required to achieve adequate serum levels may explain the apparent contradictions between reports correlating response rates and dose and those correlating serum level and response.

Use of magnesium sulphate in the anaesthetic management of phaeochromocytoma in pregnancy

The anaesthetic management of two patients with phaeochromocytoma complicating pregnancy is presented. In one patient, the operative delivery was followed by elective tumour resection at a later stage. Magnesium sulphate was used as an adjunct to all three anaesthetics, with notable success on two occasion. In one of the operative deliveries, it proved impossible to achieve adequate blood levels of magnesium, due to severe pre-existing magnesium deficiency. Hypomagnesaemia is likely to be present in such cases and must be corrected preoperatively. Magnesium sulphate is a useful adjunct to the anaesthetic management of the pregnant patient with a phaeochromocytoma provided that adequate serum levels of magnesium can be established.