Biomedical subjects
M N Dudley
Publications and source records attributed to M N Dudley.
In vitro activity of cefonicid, ceforanide, and cefazolin against Staphylococcus aureus and Staphylococcus epidermidis and the effect of human serum.
Explore the source record for details and available documents.
Antimicrobial irrigations in the prevention and treatment of catheter-related urinary tract infections.
The use, development, efficacy, and adverse effects of antimicrobial irrigation solutions for prevention and treatment of urinary tract infections in catheterized patients are reviewed. Bacteriuria occurs rapidly in catheter systems where urine is collected in an open vessel. With newer drainage systems, where the urine is collected in a closed catheter tubing-receptacle system, the incidence of bacteriuria is reduced substantially. Prophylactic continuous irrigation with various solutions has been demonstrated to be effective in decreasing the incidence of bacteriuria in open catheter drainage systems, especially for 10 days or less following catheter insertion. Prophylactic irrigation of closed catheter systems has not been demonstrated to prevent bacteriuria. Treatment of urinary tract in catheterized patients through use of an antifungal irrigation has been demonstrated to be effective in Candida cystitis. Prophylactic antimicrobial irrigations in closed catheter systems appears to be unnecessary and may promote infection with organisms resistant to the irrigating solution. Strict adherence to proper catheter care procedures is the most important factor in reducing catheter infection rates.
Tissue penetration and half-life of cefonicid.
The pharmacokinetics of cefonicid in the serum and tissues of patients undergoing open heart surgery, vaginal hysterectomy, and hip replacement was studied and compared with that of cefazolin and cefoxitin. Cefonicid achieved serum and tissue concentrations that were higher and more prolonged than those of cefazolin and cefoxitin. For cefonicid parallelism was observed between the serum and tissue concentration-time curves. Correlations of these properties to clinical efficacy were not attempted.
Clinical pharmacology of benzathine penicillin G.
Explore the source record for details and available documents.
Amphotericin B-associated hypertension.
OBJECTIVE: To report two cases of hypertension related to amphotericin B infusion. CASE SUMMARY: A 63-year-old woman with Candida albicans bacteremia and an 84-year-old man with Aspergillus fumigatus pneumonia developed hypertension within minutes of amphotericin B administration. Both patients' blood pressure returned to baseline soon after the infusion of amphotericin B was stopped. Neither patient was rechallenged. DISCUSSION: A causal relationship may exist between the administration of amphotericin B and these hypertensive episodes. Blood pressure in both patients normalized without treatment on discontinuation of the infusion. The mechanism of amphotericin B-associated hypertension is unclear but could include vasoconstricting properties of the drug or the administration of intravenous NaCl 0.9% prior to amphotericin B infusion. We recommend that intravenous NaCl 0.9% be administered following amphotericin B infusion and that the infusion be stopped if hypertensive episodes arise. CONCLUSIONS: Both acute hypertension and hypotension can occur in patients receiving amphotericin B for systemic fungal infections.
Cefotaxime: microbiology, pharmacology, and clinical use.
The microbiological activity, pharmacology, and clinical efficacy of the third-generation cephalosporin cefotaxime are reviewed. Cefotaxime has greater activity than other available first- and second-generation cephalosporins against Enterobacteriaceae. It is more active than older cephalosporins against Pseudomonas aeruginosa and Acinetobacter spp., but most strains are still considered resistant. Cefotaxime is also active against some gram-negative bacilli that are resistant to aminoglycosides, including amikacin. Cefotaxime has activity comparable with other cephalosporins against gram-positive cocci, except staphylococci and enterococci, which are resistant. Cefotaxime in combination with penicillins or aminoglycosides may be synergistic against selected gram-negative bacilli. Cefotaxime is metabolized in vivo to the desacetyl derivative, which is also microbiologically active. Cefotaxime appears to penetrate most body tissues and fluids, including cerebrospinal fluid. Clinical use of cefotaxime has resulted in response rates between 70 and 95% in most infections. The ultimate role of cefotaxime and other third-generation cephalosporins is not established since controlled clinical comparisons with standard antimicrobial regimens are lacking. Possibilities include the empiric and specific therapy of serious gram-negative bacillary infection probably in combination with a penicillin or an aminoglycoside. Cefotaxime appears to be potentially useful in the management of gram-negative bacillary meningitis.
Review of cefonicid, a long-acting cephalosporin.
The in vitro activity, pharmacokinetics, adverse effects, and clinical efficacy of cefonicid are reviewed. Also discussed are formulary considerations and bacterial resistance. Cefonicid, an investigational agent near approval, is less active than other currently available first- and second-generation cephalosporins against gram-positive cocci, particularly Staphylococcus. Cefonicid and cefamandole have similar activity that is superior to the first-generation cephalosporins against Escherichia coli, Klebsiella, Citrobacter spp., Enterobacter spp., indole-negative Proteus spp., and Providencia spp. Organisms such as Serratia marcescens, Acinetobacter, Pseudomonas, and Bacteroides fragilis are resistant to cefonicid. Despite a small volume of distribution and high protein binding, cefonicid achieves high tissue concentrations. Approximately 90% of an administered dose is excreted unchanged in the urine, and the elimination half-life is approximately four hours. Cefonicid is usually well tolerated. In treating skin infections, cefonicid was usually less effective than cefazolin against Staphylococcus aureus. In genitourinary infections, cefonicid 1 g daily (as the sodium salt) in a single dose has shown comparable efficacy to cefamandole or amoxicillin given in multiple daily doses. Based on available data, single daily dosing of cefonicid in the therapy of Staph. aureus endocarditis is not effective. In studies of patients undergoing hysterectomy, cesarean section, cholecystectomy, and colorectal surgery, cefonicid 1 g given as a single preoperative dose has produced results comparable with those of cefoxitin 1-2 g (as the sodium salt) given preoperatively and for several doses postoperatively. The major clinical uses of cefonicid will probably be as a possible cost-reducing alternative (based on a single daily dose) to currently available first- and second-generation cephalosporins for the treatment of community-acquired pneumonia and infections caused by enteric organisms. It may also be useful as a possible cost-reducing alternative to cefoxitin for prophylaxis in hysterectomy and biliary tract surgery.
Pharmacokinetics and pharmacodynamics of high-dose zidovudine administered as a continuous infusion in patients with cancer.
STUDY OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of high-dose intravenous zidovudine (ZDV). DESIGN: Phase 1, dose-escalating, unblinded study in patients with cancer. SETTING: A university-affiliated cancer treatment center. PATIENTS: Fourteen patients (6 women) with solid tumors that were unresponsive to standard therapy received 31 courses of therapy. INTERVENTIONS: Intravenous ZDV was administered in doses of 2, 3, 4, 5.5, 7, 8.5, 10, 12, 15, or 20 g/m2/day as a continuous infusion over 48 hours. Patients also received fluorouracil plus leucovorin for 24 hours before the start of and during the ZDV infusion. If no dose-limiting toxicities were encountered, subsequent doses were escalated. Blood samples were collected at 24 and 48 hours after the start of the infusion, and hourly for 4 hours after stopping the infusion. Urine was collected in five patients during the infusion and for 24 hours after stopping it. Blood for measuring peripheral white blood cells was collected before and at the end of the infusion in seven patients to measure DNA chain breaks due to incorporation of ZDV. MEASUREMENTS AND MAIN RESULTS: Zidovudine was measured in plasma by high-performance liquid chromatography and in urine fluorescence polarization immunoassay. Its incorporation into DNA was measured by determining DNA strand breakage in peripheral white blood cells using fluorescence analysis. Pharmacokinetic models were fit to plasma ZDV concentrations using extended least squares regression. Short-term high-dose ZDV was generally well tolerated, with adverse effects related to large amounts of free water administered during the infusion. The mean (SD) ZDV pharmacokinetic values were total clearance 1.44 (1.09) L/hr/kg, volume of distribution 2.72 (2.97) L/kg, and half-life 1.2 (0.6) hours. There was considerable interpatient variability in total drug clearance. Although ZDV exposure increased proportionately with increasing dose, two of three patients receiving the highest dose (20 g/m2/day) had markedly low total drug clearances. The relation between the percentage of abnormal DNA in peripheral white blood cells and zidovudine area under the plasma ZDV versus time curve was described by the Emax pharmacodynamic model. CONCLUSIONS: The pharmacokinetics of high-dose ZDV administered by continuous infusion to patients with cancer are similar to those reported with lower doses in patients with infection due to the human immunodeficiency virus. Further study of potential nonlinear pharmacokinetic behavior at doses above 20 g/m2/day is necessary. The high between-patient variability in ZDV clearance results in variable levels of exposure in vivo, and indicates the need for concentration- or effect-controlled study designs in the further evaluation of the agent's antineoplastic effects.
Maximizing patient outcomes of antiinfective therapy.
Drug treatment of infectious disease requires consideration of both short- and long-term therapy. Although in most settings patients receive antimicrobials for acute events, long-term management of certain infections with drugs that delay progression of the disease adds a new facet to pharmacotherapy. In the past, broad questions regarding efficacy were posed: a drug was evaluated as either effective or not effective for a particular disorder. The actual question is, in whom is a given drug at a given dosage effective? Antibiotic control, restriction, and pharmacokinetic dosing programs have been useful, but they are reactive as opposed to proactive. The expensive products of biotechnology and the availability of oral drugs with activity exceeding that of parenteral antimicrobials require a more expanded scope of clinical pharmacy practice where patients are identified for these therapies prospectively using statistical models based on disease and other readily identified factors. Predictor variables for patient outcomes such as retreatment with other antibiotics, rehospitalization, toxicity, and mortality following the use of new drugs should be identified. Maximizing these outcome measurements will involve strategies that integrate epidemiology and statistical modeling techniques with principles of pharmaceutical care.
Management of herpesvirus infections in the healthy host.
Human herpesvirus infections continue to be a concern in immunocompetent as well as immunocompromised hosts. They are often life threatening in the immunocompromised patient. In the healthy immunocompetent person the infections tend to be self-limited, although they can directly or indirectly cause periods of severe discomfort and disability, and their treatment can affect productivity, as shown by cost-outcome models. Treatment of primary or secondary episodes in the immunocompetent host is therefore directed toward more rapid resolution of initial and recurrent episodes, thereby limiting the impact of the infections.