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Biomedical subjects

R Quintiliani

Publications and source records attributed to R Quintiliani.

At least 271 records · Page 15Linked to original sources
PubMedDate not supplied

Potential role of trimethoprim-sulfamethoxazole in the treatment of serious hospital-acquired bacterial infections.

Although trimethoprim-sulfamethoxazole (TMP-SMZ) has become a standard agent for the treatment of a broad range of infections, it may often be overlooked as a choice for treatment of serious hospital-acquired infections. A review of the literature shows that a number of common and uncommon gram-negative and gram-positive organisms susceptible to TMP-SMZ are frequently resistant to cephalosporins. TMP-SMZ has, in addition to its exceptional microbiologic activity, pharmacokinetic characteristics that make it a potentially cost-effective alternative to third-generation cephalosporins in the treatment of serious hospital-acquired infections caused by susceptible organisms.

Bacterial Infections↗
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Comparison of the bactericidal activity of trovafloxacin and ciprofloxacin, alone and in combination with cefepime, against Pseudomonas aeruginosa.

BACKGROUND: Although ciprofloxacin exhibits more intense microbiological activity against Pseudomonas aeruginosa than does trovafloxacin, the clinical relevance of this observation remains questionable, particularly when the agents are combined with another antipseudomonal agent. METHODS: To evaluate this further, we conducted a four-way crossover trial to compare the bactericidal activities of ciprofloxacin and trovafloxacin, alone and in combination with cefepime, against three clinical isolates of P. aeruginosa. Healthy subjects received the following regimens, dosed to steady state: trovafloxacin 300 mg/24 h; ciprofloxacin 400 mg/12 h; trovafloxacin 300 mg/24 h plus cefepime 2 g/12 h, and ciprofloxacin 400 mg/12 h plus cefepime 2 g/12 h. Serum bactericidal titers were performed with each regimen. RESULTS: As monotherapy, the area under the bactericidal curve for ciprofloxacin exceeded that of trovafloxacin for all isolates. No significant difference in the overall degree of bactericidal activity was noted for two of three P. aeruginosa isolates for the combination regimens. Additionally, both combination regimens provided bactericidal activity for 100% of the dosing interval for all isolates. CONCLUSION: These results indicate that, while in vitro differences exist among these quinolones for P. aeruginosa, when a fluoroquinolone is combined with a beta-lactam, this is likely to be of little clinical significance.

Adult↗
PubMedDate not supplied

Pharmacokinetics of high-dose meropenem in adult cystic fibrosis patients.

Because patients with cystic fibrosis (CF) have pulmonary exacerbations secondary to multi-antibiotic-resistant Gram-negative bacilli, antibiotics, like meropenem, are often utilized. We studied the pharmacokinetics of meropenem (2 g i.v. administered every 8 h in clinically stable CF patients to determine if the recommended maximum doses could sustain adequate concentrations during the dosing interval. These pharmacokinetic data were similar to those obtained in non-CF populations. Using this regimen, concentrations of meropenem exceed the susceptibility breakpoint (4 microg/ml) for 50% of the dosing interval, and therefore provide optimization of the pharmacodynamic profile of the compound.

Adolescent↗
PubMedDate not supplied

Circulating tumor necrosis factor-alpha production during the progression of rat endotoxic sepsis.

The endotoxin-mediated tumor necrosis factor-alpha (TNF-alpha) induction was investigated in a rat endotoxin septic shock model. Rats were challenged intravenously with lethal doses of endotoxin. Circulating endotoxin and TNF-alpha concentrations were measured over various times following endotoxin administration. A derivative of human immunoglobulin G, 5S-IgG, was administered at various times relative to endotoxin dosing to test its anti-endotoxin activity. Results showed that endotoxin challenge initiated substantial amounts of TNF-alpha release into the rat circulatory system leading to death. A temporal pattern of TNF-alpha increases following endotoxin administration was observed; the rat plasma TNF-alpha level rapidly increased 60 min after endotoxin injection, peaked around 120 min and returned to low levels by 240 min. A rapid clearance pattern of endotoxin was also observed in rats. 5S-IgG exhibited its moderate anti-endotoxin activity by partially suppressing the endotoxin-mediated TNF-alpha release and decreasing the overall mortality only when given before triggering of TNF-alpha induction. However, this inhibitory effect of 5S-IgG on endotoxin-mediated TNF-alpha release and the resultant protective effect against endotoxin lethality rapidly diminished when 5S-IgG was administered after the occurrence of TNF-alpha induction. Collectively, these results suggest that the timing of the anti-endotoxin treatment is critical in achieving its effectiveness and imply that the endotoxin levels after the onset of the cytokine cascade is of questionable significance.

Animals↗
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Optimizing clinical outcomes by the use of pharmokinetic and pharmacodynamic principles.

Since the advent of antimicrobial chemotherapy, considerable controversy has existed as to the most appropriate method to administer antibiotics to maximize the killing of microorganisms, while minimizing toxicity to the patient. Over the past decade, data gained from animal models of infection, in vitro pharmacodynamic studies, volunteer studies and human clinical trials have enabled us to establish the best mode of drug administration to achieve these goals. The clinician should be aware that appropriate antibiotic selection and dosing depends on pharmacodynamic concepts where there is an integration of the drug's microbiological activity, pharmacokinetic properties and mode of bacterial killing.

Anti-Bacterial Agents↗
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Transitional (intravenous to oral) antibiotic therapy.

Most clinicians feel the best clinical outcome occurs when patients are treated for serious infections with injections for the entire illness. Unfortunately, this type of prescribing style results in considerable indirect costs such as those involved in increased labor (nursing, pharmacy, intravenous technician time), supplies (needles, syringes, intravenous solutions, administration sets, infusion pumps) and nosocomial bacteremia. It now appears from pharmacodynamic and pharmacoeconomic information that this traditional prescribing behavior should change in the management of many infectious diseases, particularly in those clinically stable patients who can ingest or digest a medication. With the presence of numerous antibiotics with high bioavailability, many infections in such patients can now be successfully treated with an oral agent. This review provides examples of common infections (such as community- and hospital-acquired pneumonias, intra-abdominal infections, urinary tract infections, and skin, soft tissue, and bone infections) in which oral therapy can replace parenteral agents.

Administration, Oral↗
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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.

Bacterial Infections↗
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Comparison of four methods of predicting serum gentamicin concentrations in adult patients with impaired renal function.

Four methods of predicting serum gentamicin concentrations (SGCs) in adult patients with stable impaired renal function were compared. Serum samples obtained from 17 patients receiving intravenous gentamicin therapy were assayed for gentamicin using a radioimmunoassay. Kinetic variables derived using four different methods were used to predict peak and trough concentrations. The Sawchuk-Zaske method uses individualized apparent volume of distribution (Vapp) and half-life (t1/2) derived from at least three SGCs following a given dose. The fitted method assumes Vapp equals 0.28 liters/kg lean body weight (LBW) and a t1/2 derived by a fitting technique using only one SGC. Both the Tozer and Hull methods assume Vapp equals 0.28 liters/kg LBW, and t1/2 is estimated from equations that take into account the patient's renal function (creatinine clearance). The predicted and measured SGCs for each method were compared using linear regression analysis. The prediction errors, defined as the predicted minus the measured SGC, were compared for the four methods. The correlation coefficients between the measured and predicted SGCs were significant at p less than 0.05 only for the Sawchuk-Zaske and fitted methods. For the Sawchuk-Zaske method, peak and trough r values were 0.73 and 0.91, respectively. For the fitted method, peak and trough r values were 0.53 and 0.71, respectively. No significant differences in the mean prediction errors were observed, except for the Sawchuk-Zaske method, which had significantly less mean prediction error than the Hull method. The Sawchuk-Zaske method was the most reliable and accurate pharmacokinetic technique. However, because it is more costly and less convenient than the other three methods, both the accuracy and cost should be considered when selecting a method for determining serum gentamicin concentrations for a particular patient.

Aged↗
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Pharmacokinetics of vancomycin in anuria.

After a single 1-g intravenous dose of vancomycin, the mean peak concentration in the serum of 29 anephric patients was 48.3 micrograms/ml. An initial rapid decline to 15 micrograms/ml within 3-5 hr was followed by slow elimination, with 3.5 micrograms/ml present after 18 days. Intermittent dialysis had no appreciable effect on drug levels in serum. The biphasic decline in serum concentrations of vancomycin indicates at least two-compartment pharmacokinetics in both anephric and normal patients. In anephric patients the elimination half-life was 7.5 days and the elimination rate constant was 0.32; these values were 8 hr and 10.25, respectively, in normal patients. On the basis of these results, the vancomycin regimen recommended for anephric patients is an initial 1-g intravenous dose followed by 500 mg every eight days. With these dosages peak concentrations are 49 micrograms/ml (well below reported toxic levels) and trough concentrations are 7 micrograms/ml (well above the minimal inhibitory concentrations for susceptible pathogens causing shunt infections).

Adolescent↗
PubMedDate not supplied

Comparison of the pharmacodynamic activity of cefotaxime plus metronidazole with cefoxitin and ampicillin plus sulbactam.

STUDY OBJECTIVE: To compare the pharmacokinetic and pharmacodynamic activity of three drug regimens: cefotaxime plus metronidazole, cefoxitin, and ampicillin-sulbactam against two organisms frequently isolated in intraabdominal infection, Escherichia coli and Bacteroides fragilis. DESIGN: Open-label, three-way crossover study. SETTING: Hartford Hospital Clinical Research Center. PARTICIPANTS: Nine healthy volunteers. INTERVENTIONS: Subjects received the following regimens: (1) a single 1-g intravenous dose of cefotaxime plus a single 500-mg oral dose of metronidazole; (2) two intravenous doses of cefoxitin, 2 g each dose given every 6 hours; and (3) two intravenous doses of ampicillin-sulbactam, 3 g each dose given every 6 hours. MEASUREMENTS AND MAIN RESULTS: Serum bactericidal titers and drug concentrations were measured over a 12-hour period. The cefotaxime-metronidazole regimen showed superior activity against E. coli compared with ampicillin-sulbactam and cefoxitin. The mean areas under the bactericidal activity curve (AUBC) for the three regimens were 550.2, 68.7, and 48.9, respectively (p = 0.0001). There was no significant difference in AUBC among the three regimens for B. fragilis. Serum concentrations of cefotaxime remained above the minimum inhibitory concentration (MIC) for E. coli significantly longer than did concentrations of ampicillin-sulbactam and cefoxitin (p = 0.0002 and p = 0.0023, respectively). Serum concentrations of metronidazole were still at 9 times the MIC for B. fragilis at the end of the 12-hour dosing interval; for ampicillin-sulbactam and cefoxitin concentrations remained above the MIC for one-half and less than one-fourth, respectively, of the dosing interval (p < 0.0001). The ratio of AUC:MIC was also favorable for metronidazole (212.2) compared with 63.4 for ampicillin-sulbactam and 9.2 for cefoxitin. CONCLUSIONS: The combination of cefotaxime-metronidazole, even at the relatively low doses used in this study, provides coverage against gram-negative and anaerobic pathogens that is at least as effective as that of cefoxitin and ampicillin-sulbactam. In addition, its cost is considerably less expensive than that of the other regimens.

Administration, Oral↗
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Effect of continuous arteriovenous hemodiafiltration on the pharmacokinetics of fluconazole.

In critically ill patients with acute renal failure, continuous arteriovenous hemodiafiltration (CAVHD) has become an increasing popular supportive technique. An adult with acute renal failure during CAVHD therapy received fluconazole. Drug clearance by the hemodiafilter system and its total body clearance during the CAVHD period were 23-28 ml/minute and 22 ml/minute, respectively, indicating that the rate of systemic clearance was solely dependent on CAVHD in this patient. Total body clearance, area under the curve, and half-life values for this patient closely resembled those in healthy subjects. These observations suggest that patients treated with fluconazole during CAVHD should receive standard maintenance dosages, and neither supplementation nor dosage adjustment is required.

Acute Kidney Injury↗
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Bactericidal activity of low-dose ceftizoxime plus metronidazole compared with cefoxitin and ampicillin-sulbactam.

Eighteen volunteers received ceftizoxime 1 g plus metronidazole 500 mg intravenously every 12 hours, cefoxitin 2 g intravenously every 6 hours, and ampicillin-sulbactam 3 g every 6 hours in a triple-crossover, open-label study to compare serum bactericidal titers (SBTs) against two strains of Escherichia coli and Bacteroides fragilis. Serum was analyzed for drug concentration and bactericidal activity. Ceftizoxime-metronidazole exhibited a significantly greater (p < 0.05) area under the bactericidal curve and percentage of the dosing interval with SBTs of 1:2 or above against E. coli than cefoxitin or ampicillin-sulbactam. The respective values were equal to those of ampicillin-sulbactam for one strain of B. fragilis (both greater than cefoxitin) and greater than cefoxitin and ampicillin-sulbactam for the other strain. A 1-g dose of ceftizoxime given with metronidazole 500 mg every 12 hours should be an effective alternative to standard antibiotic treatment of mixed aerobic-anaerobic bacterial infections.

Adult↗
PubMedDate not supplied

Comparison of the pharmacokinetic and pharmacodynamic activity of piperacillin and mezlocillin.

STUDY OBJECTIVE: To compare serum bactericidal activity over time and pharmacokinetics resulting from single doses of piperacillin (PIP) and a single dose of mezlocillin (MEZ). DESIGN: Open-label, randomized, three-way crossover study. SETTING: Hartford Hospital Clinical Research Center. PATIENTS: Nine healthy volunteers. INTERVENTIONS: Subjects received single doses of PIP 3 and 4 g/70 kg, and a single dose of MEZ 5 g/70 kg. MEASUREMENTS AND MAIN RESULTS: Test organisms were two clinical isolates of Pseudomonas aeruginosa. Pharmacodynamic analysis revealed that PIP 4 g had 2- to 3-fold higher peak serum bactericidal activity at the end of infusion and 4- to 5-fold higher activity at 0.5 hour than did MEZ 5 g, and also provided approximately 1 hour additional activity over MEZ 5 g. Pharmacokinetic analysis revealed that serum concentrations resulting from PIP 4 g remained above the minimum inhibitory concentration of our test strains almost twice as long as MEZ 5 g. CONCLUSION: Since mezlocillin 5 g every 8 hours is currently proving to be effective at many institutions, and since piperacillin 4 g demonstrates superior pharmacokinetic and pharmacodynamic activity, we believe that piperacillin 4 g every 8 hours could be used instead, with resulting cost savings.

Adult↗
PubMedDate not supplied

Oral absorption of trimethoprim-sulfamethoxazole in patients with AIDS.

STUDY OBJECTIVE: To determine the bioavailability of trimethoprim-sulfamethoxazole (TMP-SMX) in patients infected with the human immunodeficiency virus (HIV). DESIGN: Open-label, randomized, two-way crossover trial. SETTING: Outpatient clinical research center affiliated with a community-based teaching hospital. PATIENTS: Ten individuals diagnosed with the acquired immunodeficiency syndrome (AIDS) with CD4+ counts less than 200 cells/mm3, receiving TMP-SMX one double-strength tablet 3 times/week as prophylaxis for Pneumocystis carinii pneumonia (PCP), and without documented gastroenteropathy or diarrhea agreed to participate in the trial. One patient withdrew from the study secondary to development of symptomatic PCP. Data were available for analysis from the remaining nine subjects. INTERVENTIONS: Participants received TMP 160 mg and SMX 800 mg orally or intravenously during two study periods. Following dose administration, blood samples were collected at predetermined time points over 36 hours. MEASUREMENTS AND MAIN RESULTS: Analysis of TMP-SMX pharmacokinetic parameters (half-life, total body clearance, area under the serum concentration versus time curve, and peak concentration) failed to reveal any significant differences between intravenous and oral preparations. The calculated bioavailabilities of oral TMP and SMX (mean +/- SD) were 102.7% +/- 19.8% and 109.4% +/- 19.4%, respectively. CONCLUSION: The absorption of TMP-SMX is not adversely affected by HIV infection in the absence of HIV-induced gastroenteropathy or diarrhea.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Cost of oral antibiotic therapy.

Many bacterial infections can be managed effectively with oral agents rather than parenteral therapy, significantly reducing treatment costs. With renewed interest in oral therapy, and with the importance of cost containment in the managed care environment, it is necessary to evaluate costs associated with different oral antimicrobials. Comparison of per-dose cost and baseline treatment cost (cost/dose x doses/day x days of treatment) is straightforward. More difficult to determine is the overall treatment cost, which is influenced by probabilities that therapy will be effective, safe, and complete. Tolerability, complexity of dosage regimen, and potential for drug-drug interactions may all affect therapeutic efficacy and overall cost. Compared with older agents, newer antibiotics are generally better tolerated and less likely to produce adverse reactions, resulting in better patient compliance, greater efficacy, and often lower overall cost of antimicrobial therapy.

Administration, Oral↗
PubMedDate not supplied

Pharmacoeconomic impact of once-daily aminoglycoside administration.

A retrospective cost analysis compared hospital costs of standard gentamicin dosing and once-daily regimens in 1127 patients. Hospital costs compared were drug/supply/preparation/administration (DSPA; $4.56/500 mg once-daily dose and $3.32/100 mg every 8 hrs standard dose); therapeutic drug monitoring (TDM) ($25/gentamicin level); and nephrotoxicity management. The mean length of therapy was 4.5 days with both regimens. The mean number of blood samples drawn to measure drug levels was 0.65 for once-daily dosing and 1.7 for standard dosing. Mean DSPA and TDM costs/patient for a 4.5-day course of once-daily therapy were $20.52 and $16.25, respectively ($36.77/course of therapy). In comparison, estimated mean DSPA and TDM costs for 4.5 days standard therapy were $44.82 and $42.50, respectively ($87.32/course of therapy). We observed an overall reduction in nephrotoxicity from approximately 4% to 1.2% with the once-daily program, resulting in a nephrotoxicity management cost reduction from $182 to $55/patient exposed to aminoglycosides. The once-daily program resulted in a 58% reduction in aminoglycoside-associated hospital cost and a nephrotoxicity management savings of 70%/patient.

Anti-Bacterial Agents↗