Endotypes of difficult-to-control asthma in inner-city African American children.

African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6-17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population.

Utility of a transdermal delivery system for antihypertensive therapy. Part 1.

A retrospective evaluation of patient-level Medicaid claims data from two states was undertaken to discern the fiscal utility of transdermally delivered clonidine versus both the oral formulation of clonidine and oral formulations of eight other antihypertensive agents. In the first phase of our two-part study, we compared paid claims data (n = 1,135) from Florida for transdermal and oral clonidine. Multivariate regression analysis was used to evaluate the incremental impact of six variables on health-care expenditures in the first year after patients were given a diagnosis of hypertension. These variables were: age, gender, prior utilization of medical services, regimen complexity, and dosage formulation. Patients prescribed transdermal clonidine experienced a significant (p less than or equal to 0.001) increase in prescription expenditures and significant reductions in the use of physician (p less than or equal to 0.05), laboratory (p less than or equal to 0.10), and hospital (p less than or equal to 0.05) services. Moreover, savings were maximized (p less than or equal to 0.001) where multi-drug regimens incorporated the transdermal delivery system. In the second phase of our study we compared paid claims data (n = 8,894) from South Carolina for transdermal clonidine and for nine oral antihypertensive agents: atenolol, captopril, clonidine, diltiazem, enalapril, metoprolol, prazosin, terazosin, and verapamil-SR. Once again, regression analysis was used, this time to evaluate the incremental impact of five variables on health-care expenditures in the first year post diagnosis: age, gender, prior utilization of medical services, regimen complexity, and Medication Possession Ratio (MPR), an index of compliance. The data from part 2 of our study revealed that patients assigned a b.i.d. oral antihypertensive agent experienced a significant reduction (p less than or equal to 0.05) in MPR and a significant (p less than 0.05) increase in health-care expenditures when compared to patients prescribed the transdermal delivery system and to patients prescribed once-daily oral medications. These data confirm previous findings concerning the impact of complicated dosing regimens on compliance in hypertensive patients. In this two-part paper we report the data from both phases of our study.

Citrobacter urinary tract infections in children.

BACKGROUND: Citrobacter species have been described as the etiologic agents in cases of bacteremia, meningitis, diarrhea and brain abscess, but little is known of their role as a cause of urinary tract infections in children. The purpose of this study was to define the role of Citrobacter species in pediatric urinary tract infections. METHODS: The project consisted of a retrospective chart review of microbiologic and medical records of patients younger than 18 years of age with urine cultures positive for Citrobacter species during a 3-year period. RESULTS: Thirty-four patients with 37 infections were included in the review. The average patient age was 6.9 years (range, 1 month to 18 years) and 71% were female. Fifty-six percent of the patients had urinary tract/renal anomalies or neurologic impairment and 26% represented nosocomial infections. Thirty-seven percent of patients were asymptomatic at the time of diagnosis, whereas 63% complained of at least one of the following findings: gastrointestinal symptoms; dysuria; fever; incontinence; penile/vaginal discharge; frequency; flank pain; and hematuria. Twenty-six of the isolates were Citrobacter freundii and 11 were Citrobacter koseri. Blood cultures were obtained in 9 patients and all were negative for Citrobacter isolates. CONCLUSIONS: Although it is uncommon Citrobacter can cause urinary tract infections in the pediatric population, which occur more frequently in children with underlying medical conditions. It appears that treatment similar to that of other gram-negative enteric organisms is the most prudent approach to these children until more information can be gathered.

Effect of health education in promoting prescription refill compliance among patients with hypertension.

A multifactorial health-education program designed to enhance compliance with a once-daily regimen of atenolol was evaluated among 453 patients enrolled in health maintenance organizations (HMOs). The initiation of the 180-day study period was used to classify patients as either new or existing cases of hypertension. In turn, patients in these two categories were randomly assigned to a control or an experimental group. Patients assigned to the experimental groups received an enrollment kit upon exercising their initial prescription (new patients) or their first refill request (existing patients). The kit contained: a 30-day supply of atenolol; an educational newsletter about hypertension; information on nutrition and life-style changes; and an explanation of the intent and content of the program. Before the next scheduled prescription-refill date, each patient was contacted by telephone to inquire about his or her experience with the therapy and to stress the importance of adherence to the regimen. Each month thereafter, the newsletter and an enclosed prescription-refill reminder were mailed to each patient. The medication possession ratio, defined as the number of days' supply of atenolol obtained by a patient during the 180-day study period, was significantly (P less than or equal to 0.001) enhanced for the new and existing experimental groups relative to the control groups. Multiple regression analyses revealed that enrollment in the health-education program increased the number of days' supply of atenolol obtained by existing patients by 27 (P less than or equal to 0.001), and by new patients by 40 (P less than or equal to 0.001).

Effectiveness of the C Cap in promoting prescription refill compliance among patients with glaucoma.

In an attempt to increase patient compliance with a dosing regimen, prescriptions for topical solutions of glaucoma medication were refilled using the C Cap, a memory aid designed to help patients to remember to instill the medication as prescribed. A comparison of the number of prescription refills requested by 121 patients with glaucoma showed that patients who received the C Cap requested significantly more refills in the six months after receiving the C Cap than before and requested significantly more refills than did patients who did not receive the C Cap.

Effect of pharmaceutical formulation for antihypertensive therapy on health service utilization.

A significant factor in the management of hypertension is the extent to which patients comply with the treatment regimen. A retrospective analysis was undertaken to determine the relationship between antihypertensive formulation, regimen compliance, and the utilization of health care services. Data for this analysis were derived from the state of South Carolina's Medicaid computer archive. The study population consisted of 1000 randomly selected patients initially prescribed one of the following antihypertensive regimens as monotherapy: atenolol once daily, captopril BID, oral clonidine BID, transdermal clonidine once weekly, diltiazem BID, enalapril BID, metoprolol BID, prazosin BID, terazosin once daily, and sustained-release verapamil once daily. Multivariate regression analysis was used to determine the incremental influence of selected demographic characteristics, use of medical services before diagnosis of hypertension, initial antihypertensive medication, medication possession ratio for antihypertensive therapy, and number of maintenance medications for diseases other than hypertension on post-period health care expenditures. The results indicated that patients initially prescribed antihypertensive medication requiring once-daily or once-weekly administration experienced an increased utilization of antihypertensive medication, needed fewer changes in their therapeutic regimen, and far less need for concomitant therapy for blood pressure control compared with those prescribed a BID regimen. Patients in the once-daily or once-weekly groups also used significantly fewer physician, hospital, and laboratory services (P < or = 0.05).

Pharmacoeconomics of piperacillin/tazobactam and imipenem/cilastatin in the treatment of patients with intra-abdominal infections.

Costs involved in using piperacillin 4 g/tazobactam 500 mg, given as intermittent intravenous infusions every 8 hours, were compared with those for imipenem/cilastatin 500 mg, given as intermittent intravenous infusions every 6 hours, for the treatment of patients with gangrenous or perforated appendicitis. A total of 88 patients were included in our cost analyses: 42 patients in the piperacillin/tazobactam group and 46 patients in the imipenem/cilastatin group. Durations (mean +/- SD) of antibiotic therapies were 7.8 +/- 3.3 days and 7.1 +/- 2.6 days for the piperacillin/tazobactam and imipenem/cilastatin groups, respectively. No statistical significance was found for the difference in duration of therapy (P = 0.376). Total drug treatment costs were $538.83 +/- $385.33 for the piperacillin/tazobactam group and $687.66 +/- $345.37 for the imipenem/cilastatin group. This difference in treatment cost was statistically significant (P = 0.0001). The need for laboratory tests and the use of other medications were not different between the two groups. Total hospital-days charges were higher for the piperacillin/tazobactam group ($18,339.76 +/- $6090.38) compared with the imipenem/cilastatin group ($16,150.00 +/- $5088.60) (P = 0.052). These findings suggest that length of hospital stay should be the economic focus of antibiotic therapy.

Meropenem versus tobramycin with clindamycin in the antibiotic management of patients with advanced appendicitis.

BACKGROUND: Meropenem (MP), a new carbapenem antibiotic, has excellent antimicrobial activity against the enteric flora commonly encountered in acute appendicitis. Although similar to imipenem, it may have clinical advantages. STUDY DESIGN: We compared patients with advanced appendicitis (gangrenous or perforated) treated with 1,000 mg MP every eight hours with those given the combination of tobramycin 5 mg/kg/day at eight hour intervals and clindamycin 900 mg every eight hours. Both treatments were given intravenously. Patients were randomized to either group of the double-blind study. RESULTS: Of 129 evaluable cases, 63 received MP and 66 received both tobramycin and clindamycin (T/C). The two groups were similar in age, sex, and severity of disease. The mean number of days of postoperative fever (MP = 3.1 +/- 1.7 SD compared to T/C = 4.4 +/- 2.2 SD, p < or = 0.01), days of antibiotic therapy (MP = 6.1 +/- 1.6 SD compared to T/C = 7.3 +/- 2.2 SD, p = 0.01), and therefore hospital stay (MP = 8.0 +/- 3.5 SD compared to T/C = 9.4 +/- 2.6 SD, p < 0.01) were significantly better for patients treated with MP. No difference was found between the numbers of failures in each group (MP = 5 compared to T/C = 6). CONCLUSIONS: This study demonstrates a small but significant reduction (approximately one day) in post-operative fever, duration of antibiotic treatment, and hospital stay for patients treated with MP compared to those treated with T/C.

Pharmacokinetics of peptide T in patients with acquired immunodeficiency syndrome (AIDS).

1. The pharmacokinetics of Dala1-peptide T-NH2 (peptide T) was determined during phase I clinical trials in patients with acquired immunodeficiency disease (AIDS) and AIDS related complex (ARC). Drug levels were determined by specific RIA, and in some cases with HPLC analysis, after intravenous (i.v.) or intranasal (i.n.), via metered sprayer, administration. 2. The plasma kinetics appeared to be bi-phasic with a first compartment half-life of 30 to 60 minutes and a second plasma clearance rate of 4 to 6 hours, observed for both routes of administration. Peptide T, in one individual was confirmed to be present at 6 hrs in plasma, determined after HPLC isolation followed by specific RIA. 3. Bioavailability, determined for a 2 mg test dose in six individuals was 9.3 +/- 6.9 nmol/L. Peak plasma levels of 41 +/- 30 nmol/L after 10 mg i.n., 2.8 +/- 5.9 nmol/L after 2 mg i.n., and 0.13 +/- 0.07 nmol/L after 0.4 mg i.n. were observed. In two individuals tested, peptide T was detected in CSF at levels 20% of the corresponding plasma level 90 and 145 minutes post i.v. administration. Peptide T was not detected in urine. I.N. administration was well tolerated for times up to 21 months.

Piperacillin-tazobactam pharmacokinetics in patients with intraabdominal infections.

STUDY OBJECTIVE: To determine the appropriate compartmental and noncompartmental pharmacokinetic parameters for intravenous piperacillin and tazobactam. DESIGN: Sequential selection of patients entered into a randomized, open-label clinical efficacy trial. SETTING: Los Angeles County-University of Southern California Medical Center. PARTICIPANTS: Sequential sample of 18 patients admitted for intraabdominal infections and consented into a comparative antibiotic trial. INTERVENTIONS: Patients received piperacillin 4 g plus tazobactam 500 mg by intravenous intermittent infusion every 8 hours. MEASUREMENTS AND MAIN RESULTS: The estimated noncompartmental pharmacokinetic parameters (mean +/- SD) for piperacillin and tazobactam, respectively, were as follows: maximum concentration in plasma 218.7 +/- 48.9 micrograms/ml and 27.8 +/- 9.1 micrograms/ml; half-life 1.07 +/- 0.22 hours and 1.00 +/- 0.27 hours; elimination rate constant 0.67 +/- 0.13 hr-1 and 0.73 +/- 0.18 hr-1; area under the concentration-time curve from zero hour to infinity 288.5 +/- 71.25 mg.hr/L and 36.3 +/- 9.55 mg.hr/L; total plasma clearance 14.75 +/- 3.93 L/hour and 14.78 +/- 4.39 L/hour; renal clearance 5.69 +/- 1.94 L/hour and 7.85 +/- 3.37 L/hour; volume of distribution at steady state 21.00 +/- 4.18 L and 22.47 +/- 8.27 L; and mean residence time 1.72 +/- 0.29 hours and 1.79 +/- 0.35 hours. CONCLUSION: Our findings were similar to those in other surgical patient models. The two-compartmental model best described piperacillin and tazobactam disposition in our patients. Bayesian analyses of the two-compartment models of piperacillin and tazobactam were able to predict trough, peak, and 2-hour postadministration levels without bias.

Analysis of cefepime tissue penetration into human appendix.

Cefepime is a new extended-spectrum cephalosporin with gram-positive and gram-negative coverage including Staphylococcus aureus and Pseudomonas aeruginosa. We evaluated the drug's plasma, peritoneal fluid, and appendix tissue concentrations in patients with a postoperative diagnosis of perforated or gangrenous appendicitis. Patients 18 years of age or older were randomly assigned to receive either cefepime 2 g every 12 hours plus metronidazole 500 mg every 6 hours intravenously, or gentamicin 1.5 mg/kg plus clindamycin 900 mg every 8 hours intravenously. During surgery, appendix tissue, plasma, and peritoneal fluid samples were obtained, and frozen at -70 degrees C for high-pressure liquid chromatographic analysis. Thirty-five patients with perforated (26) or gangrenous (9) appendicitis had concentrations acceptable for analysis. The mean time between the administration of cefepime and the time of sampling (referred to as delta time) was 5.99 +/- 3.75 hours (mean +/- SD). The values for plasma (n = 34), tissue (n = 33), and peritoneal fluid (n = 25) concentrations were 16.27 +/- 21.87 micrograms/ml, 4.84 +/- 6.15 micrograms/g, and 14.4 +/- 22.84 micrograms/ml, respectively. The appendix tissue:plasma ratio was 0.66 +/- 0.52 and the peritoneal fluid:plasma ratio was 0.66 +/- 0.51. Spearman rank correlations indicated statistically significant correlations between plasma concentration (r = -0.889; p less than 0.0001), peritoneal fluid concentration (r = -0.783; p = 0.0002), and appendix tissue concentration (r = -0.704; p = 0.0016) versus delta time.(ABSTRACT TRUNCATED AT 250 WORDS)

Cost analysis of antibiotics in the management of perforated or gangrenous appendicitis.

Costs associated with treating patients for gangrenous or perforated appendicitis were compared. Patients received single agent therapy with cefoperazone or cefamandole or combination antibiotics consisting of clindamycin and serum level-adjusted gentamicin. Forty-eight patients received cefamandole, 47 received cefoperazone, and 52 received combination clindamycin and gentamicin. Costs to the pharmacy for drugs were greater for the combination therapy; however, the higher failure rate associated with the cephalosporins created greater expenses for the single agent therapy than for combination therapy.

Stability of granisetron hydrochloride in a disposable elastomeric infusion device.

The stability and sterility of granisetron hydrochloride in 5% dextrose injection or 0.9% sodium chloride injection when stored in a disposable elastomeric infusion device were studied. Granisetron was diluted to 0.02 mg/mL (as the hydrochloride salt) in 5% dextrose chloride injection. The solution was placed in the drug reservoir of a disposable elastomeric infusion device and refrigerated at 4 degrees C for 14 days. A total of eight pumps were prepared, four containing granisetron 0.02 mg/mL in 5% dextrose injection and four containing granisetron 0.02 mg/mL in 0.9% sodium chloride injection. The solutions were assayed for granisetron concentration by stability-indicating high-performance liquid chromatography at 0 hours, 24 hours, 48 hours, 7 days, and 14 days. Each solution was inspected for clarity, color, and precipitation, and sterility testing was performed. Throughout the study, the mean concentration of granisetron remaining was more than 92% of the initial concentration both in 5% dextrose injection and in 0.9% sodium chloride injection. Individual solutions in 0.9% sodium chloride injection consistently maintained more than 90% of the initial drug concentration for only seven days. No microbial growth was detected. No precipitation, color change, or haziness was seen. Granisetron 0.02 mg/mL (as the hydrochloride salt) was stable and free of microbial growth in 0.9% sodium chloride injection for up to 7 days and stable and free of microbial growth in 5% dextrose injection for up to 14 days when stored at 4 degrees C in a disposable elastomeric infusion device.

Pathophysiology and treatment of psoriasis.

The pathogenesis and treatment of psoriasis are reviewed. Psoriasis is characterized by defects in the normal cycle of epidermal development that lead to epidermal hyperproliferation, altered maturation of skin cells, and vascular changes and inflammation. The condition typically manifests as areas of thickened, flaky, silvery white and reddened skin that may hurt, itch, and bleed. Biochemical markers of psoriasis are changes in levels of keratins, keratinocyte transglutamase, migration inhibitory factor-related protein, skin-derived antileukoproteinase, involucrin, small protein rich protein 2, filaggrin, and cytokines. Types of psoriasis that may be clinically encountered include plaque psoriasis, guttate psoriasis, erythrodermic psoriasis, and pustular psoriasis. Psoriasis is believed to be genetically linked but can also be triggered by mechanical, ultraviolet, and chemical injury; various infections; prescription drug use; psychological stress; smoking; and other factors. Topical treatment of psoriasis is usually the first line of therapy. Topical treatments consist of emollients and keratolytic agents, anthralin, coal tar, corticosteroids, vitamin D3 analogues, topical retinoids, and topical psoralens plus ultraviolet A (UVA) light. In patients who do not respond adequately to topical therapy, oral or injectable therapy, such as oral retinoids, methotrexate, cyclosporine, tacrolimus, and oral psoralens plus UVA light, may be warranted. Patients receiving systemic treatments should be carefully monitored for adverse effects and drug-drug interactions. Drug therapy is the mainstay of the treatment of psoriasis. The potential adverse effects and interactions necessitate vigilant monitoring.

Pharmacokinetics of aztreonam in critically ill surgical patients.

The pharmacokinetics of aztreonam in critically ill surgical patients with serious gram-negative infections were studied. Blood samples were taken before and at 30 minutes, 2.5 hours, and 5 hours after a dose of aztreonam 2 g i.v. every six hours. All patients had received at least two aztreonam doses before the dosage interval being studied. Aztreonam concentrations were measured by high-performance liquid chromatography. Aztreonam's pharmacokinetics, the severity of illness, and patient outcomes were examined. A total of 28 patients with 111 serum aztreonam concentrations were included in the analysis. The patients were young (mean age, 35 years) and predominantly male. The mean APACHE II score was 19.3, and 22 patients had sepsis. Four patients died. The mean volume of distribution (V) of 0.35 L/ kg was nearly twice the previously reported steady-state value for healthy volunteers (0.18 L/kg) and was highly variable. A slightly higher than normal mean V, 0.22 L/ kg, was seen in a subset of six patients whose infection occurred earlier in their intensive care and who had lower APACHE II scores. While with some antibiotics the elevated V would imply difficulty in achieving therapeutic drug levels, 99 (89%) of the 111 concentrations were at or above the in vitro susceptibility breakpoint of 8 micrograms/mL. Despite observations of markedly increased and highly variable V in critically ill surgical patients, a standard dosage of aztreonam was usually sufficient to maintain adequate serum drug levels.

Development of a modified live, canine origin parvovirus vaccine.

A modified live, canine origin parvovirus vaccine was tested for safety, efficacy, and clinical performance. The vaccine protected dogs from challenge of immunity with canine parvovirus (CPV) that caused clinical illness in all nonvaccinated dogs. Vaccinates all developed CPV serum neutralization antibody titers, with a mean value of 1,664. Challenge virus was not isolated from vaccinates, but feces from nonvaccinated dogs were CPV-positive for up to 4 days following challenge. In a pathogenicity test, dogs inoculated orally with 10 times the label dose remained clinically normal. In a reversion-to-virulence test, the vaccine strain remained nonpathogenic through 6 passages in seronegative test dogs. An immunologic interference test demonstrated that test dogs developed antibodies for all antigens in a combined canine distemper virus-adenovirus 2-parainfluenza virus-parvovirus vaccine and a Leptospira interrogans serovars canicola and icterohaemorrhagiae bacterin. A total of 1,796 doses of the multivalent preparation was administered in a field study, with veterinary practitioners reporting 36 local and 5 generalized reactions.

A cost comparison of intramuscular versus intravenous imipenem.

Previously reported clinical trials of imipenem-cilastatin 500 mg given intravenously every 6 hours (intravenous group) and imipenem-cilastatin 750 mg given intramuscularly every 12 hours (intramuscular group) were analyzed for relative cost savings. Acquisition costs were significantly higher for the intravenous group for intravenous supplies (30.6 +/- 7.9 dollars) when compared to the intramuscular group (0.98 +/- 0.03 dollars) (p less than 0.05). Also, significantly higher cost (p less than 0.05) was noted for salaries of pharmacists and technicians for manufacturing in the intravenous group (5.8 +/- 1.5 dollars) as compared to the intramuscular group (2.4 +/- 0.7 dollars). Nursing administration costs were greater for the intramuscular group (15.6 +/- 4.8 dollars) when compared to the intravenous group (11.7 +/- 3.0 dollars). Incorporating all appropriate costs, the mean total drug therapy costs (TRX$) were significantly greater (p less than 0.01) for the intravenous group (458.17 +/- 175.17 dollars) as compared to the intramuscular group (298.0 +/- 114.76 dollars). Thus, the dosing of imipenem-cilastatin 750 mg intramuscularly every 12 hours is a more cost effective method of drug delivery with equal efficacy and safety when compared to imipenem-cilastatin 500 mg given intravenously every 6 hours.