Common risk difference test and interval estimation of risk difference for stratified bilateral correlated data.

Bilateral correlated data are often encountered in medical researches such as ophthalmologic (or otolaryngologic) studies, in which each unit contributes information from paired organs to the data analysis, and the measurements from such paired organs are generally highly correlated. Various statistical methods have been developed to tackle intra-class correlation on bilateral correlated data analysis. In practice, it is very important to adjust the effect of confounder on statistical inferences, since either ignoring the intra-class correlation or confounding effect may lead to biased results. In this article, we propose three approaches for testing common risk difference for stratified bilateral correlated data under the assumption of equal correlation. Five confidence intervals of common difference of two proportions are derived. The performance of the proposed test methods and confidence interval estimations is evaluated by Monte Carlo simulations. The simulation results show that the score test statistic outperforms other statistics in the sense that the former has robust type I error rates with high powers. The score confidence interval induced from the score test statistic performs satisfactorily in terms of coverage probabilities with reasonable interval widths. A real data set from an otolaryngologic study is used to illustrate the proposed methodologies.

Tests for 2 x K contingency tables with clustered ordered categorical data.

Ordered categorical data summarized in a 2 x K table usually consist of two-sample multinomial or K-sample binomial observations. In analysing these data, we usually assign scores to the K columns and perform a testing for the equality of two multinomial distributions in the former case and no trend among K binomial proportions in the latter case. Among the most popular score tests are the Wilcoxon rank sum test and the Armitage's linear trend test. In this paper we extend the score tests to be used for clustered data under diverse study designs. Our methods do not require correct specification of the dependence structure within clusters. The proposed tests are based on the asymptotic normality for large number of clusters and are a generalization of the standard tests used for independent data. Simulation studies are conducted to investigate the finite-sample performance of the new methods. The proposed methods are applied to real-life data.

Cost-effectiveness of sparfloxacin compared with other oral antimicrobials in outpatient treatment of community-acquired pneumonia.

We examined the cost-effectiveness of sparfloxacin compared with other selected oral antimicrobials in outpatient treatment of community-acquired pneumonia (CAP) using clinical pathway-based decision analysis. Cost estimates were obtained from medical claims databases and Medicare reimbursement schedules. Probability estimates were derived from published clinical trials, the medical literature, and clinical expert opinion. Overall adjusted efficacy rates were 89% for sparfloxacin, 79.4% for azithromycin, 77.8% for clarithromycin, 73% for cefaclor, 70.8% for amoxicillin-clavulanic acid, and 69% for erythromycin. The expected total cost/CAP episode of treatment with sparfloxacin was $216.07 compared with $258.97, $297.08, $345.75, $389.80, and $395.93 for azithromycin, clarithromycin, erythromycin, amoxicillin-clavulanic acid, and cefaclor, respectively. Therapy with sparfloxacin for managing CAP is cost effective-relative to other commonly prescribed antibiotics, resulting in net cost savings.

Cefaclor into the millennium.

We review the discovery and development of the cephalosporins and subsequently cefaclor. Cefaclor is active against a wide range of commonly encountered bacterial pathogens, acting by inhibiting cell wall synthesis. Its in vitro activity compares favourably with other beta-lactam antibiotics. Its pharmacokinetic properties indicate that an 8-hourly dosing schedule is appropriate. In addition a delayed release formulation allowing twice daily dosage has been developed. The efficacy of both formulations of cefaclor has been verified by many clinical trials. Cefaclor has been widely used in infections of the respiratory tract (including otitis media), urinary tract and soft tissues. The results of therapy are summarized. The low incidence of adverse events is highlighted and the beneficial influence of this on compliance is described. Finally, the pharmaco-economics of cefaclor are considered.

[Treatment of lower respiratory tract infections in the elderly]. / Lecheniie infektsil nizhnikh dykhatel'nykh putel u lits pozhilogo vozrasta.

Sixty outpatients at the age of 65 to 75 years with exacerbated chronic bronchitis were treated with antibiotics: amoxycillin/clavulanic acid (20 patients), cefaclor (20 patients) and ciprofloxacin (20 patients). The treatment course in all the cases was 5 days. Bacteriological tests of the sputum specimens and estimation of the isolate antibiotic susceptibility by the disk diffusion method were applied to all the patients before and after the treatment. 73 per cent of the patients had mixed infection. The microflora mainly included various species of streptococci highly susceptible to the drugs (54 per cent) as well as highly susceptible strains of pneumococci and hemophilic bacilli (33 and 17 per cent respectively). Atypical microflora was detected in 10 per cent of the cases. Pseudomonas aeruginosa strains were isolated in 2 cases. Acinetobacter sp. slightly susceptible only to ciprofloxacin was isolated in 1 case. Citrobacter sp. slightly susceptible to cefaclor and moderately susceptible to ciprofloxacin was detected in 1 case. Enterobacter sp. moderately susceptible only to ciprofloxacin was isolated in 1 case. A positive factor was moderate susceptibility of Proteus mirabilis to all the three drugs. In 24 patients (the average age of 54.7 years) the pharmacokinetics of ofloxacin administered under 2 different regimens was studied. The drug was used in a single dose of 400 mg once a day (group 1) or in a dose of 200 mg twice a day (group II) followed by estimation of the drug concentration in the blood and sputum. The pathogen eradication was stated in 61.5 and 72.7 per cent of the patients in groups I and II, respectively. By the results of the treatment with the use of the above mentioned antibiotics in the elderly patients fluoroquinolones should be considered preferable from the clinical and pharmacoeconomic viewpoints.

Accelerated conditions for stability assessment of bulk and formulated cefaclor monohydrate.

The stability of cefaclor monohydrate drug substance and formulated products was studied under accelerated conditions in order to provide a rapid indication of differences that might result from a change in manufacturing process or source of the sample. The USP stability-indicating related substances assay was used to assess the extent of sample degradation. An Arrhenius study of drug substance stability from 45 to 70 degrees C predicted a degradation rate consistent with that observed in room-temperature studies. Qualitative degradation profiles of samples held at 65 degrees C for 2 weeks were also very similar to those of samples held at room temperature for 2 years. Based on these results, additional studies were conducted at 65 degrees C for 2 weeks on drug substance and formulated product samples. Stability differences were observed among some capsule formulations that had also exhibited real time differences. In some studies, rapid degradation after 5 days was observed at 65 degrees C followed by a slower rate from 5 to 15 days. Similar behavior was observed for cefaclor monohydrate containing high amounts of amorphous cefaclor, suggesting that differences in amorphous content could be an explanation for stability differences observed in various samples. The accelerated conditions were shown to differentiate samples and can provide a rapid indication of relative stability.

Roxithromycin versus cefaclor in lower respiratory tract infection: a general practice pharmacoeconomic study.

An economic evaluation comparing roxithromycin 150mg twice daily and cefaclor 250mg thrice daily in the treatment of lower respiratory tract infections (LRTI) was undertaken as part of a randomised clinical trial in New Zealand general practice. The observed statistically significant difference in adverse events, withdrawal rates and extra treatment courses in favour of roxithromycin in the clinical study was translated into medical cost savings. Treatment failures, withdrawals or adverse events resulted in additional costs for 11 of 120 (9%) patients receiving roxithromycin and 19 of 118 (16%) patients receiving cefaclor. In these cases (treatment failures, withdrawals, adverse effects) additional antibiotics and general practitioner visits were required 3 times more often and the cost of additional medication for treating failure or adverse effects was 3 times higher for patients treated with cefaclor than for patients receiving roxithromycin. The total direct medical cost per patient treated with roxithromycin was $NZ9.37 lower (on an incremental basis) than for patients treated with cefaclor, despite a higher drug acquisition cost. An estimate of $NZ656 000 per year in total savings in direct medical costs could be made in New Zealand if roxithromycin were to replace all cefaclor prescriptions in the treatment of LRTI.

Pharmacy-enforced outpatient drug treatment protocols: a case study of Medi-Cal restrictions for cefaclor.

OBJECTIVE: To evaluate whether a pharmacy-enforced treatment protocol successfully limited the use of a high-cost medication to high-risk patients. DESIGN: A case study cost-effectiveness analysis was conducted to evaluate a treatment protocol for cefaclor. Episodes of care were defined, healthcare expenditures for all services were aggregated, and demographic data were retrieved from a five percent random sample of California Medicaid (Medi-Cal) recipients. Data were available for episodes occurring before cefaclor was made available under Medi-Cal. SETTING: Medi-Cal added cefaclor to its formulary, limiting its use to patients over 50 years of age with lower respiratory tract infections (LRTIs). The unit of analysis was an episode of outpatient antibiotic treatment. PATIENTS: Confirmed LRTI episodes and unconfirmed LRTI cefaclor episodes were analyzed, including multiple episodes of treatment for individual patients. A total of 7855 non-cefaclor LRTI episodes and 2556 cefaclor episodes were analyzed. MAIN OUTCOME MEASURES: The primary outcome measures were healthcare expenditures three months after the initiation of antibiotic therapy, differentiated by type of service. RESULTS: Physicians directed cefaclor toward higher-risk patients over age 50 years, even in unconfirmed LRTI episodes. Cefaclor use was estimated to reduce posttreatment costs by $388 per patient (p < 0.001), primarily because of reduced hospital expenditures of $366 (p < 0.001). CONCLUSIONS: Pharmacy-enforced outpatient drug treatment protocols may be a viable alternative to restrictive formularies and prior authorization. In the case of cefaclor, the Medi-Cal treatment protocol appeared to allow high-risk patients better access to a high-cost medication while reducing total posttreatment costs.

Serum sickness in children after antibiotic exposure: estimates of occurrence and morbidity in a health maintenance organization population.

The computerized outpatient records of the Harvard Community Health Plan, a 230,000-member health maintenance organization, were used to determine the frequency with which serum sickness is recognized in the practice setting after exposure to antibiotics. The medical records of 3,487 children who had been prescribed cefaclor or amoxicillin were searched in December 1986 for coded diagnoses of serum sickness and related conditions. Diagnoses were validated by blinded review of dictated and written office notes. There were 12 cases of serum sickness in 11,523 child-years. During this time, these children were prescribed 13,487 courses of amoxicillin, 5,597 courses of trimethoprim-sulfamethoxazole (TMP-SMZ), 3,553 courses of cefaclor, and 2,325 courses of penicillin V. Serum sickness was considered to be antibiotic-related if it occurred within 20 days of initiation of antibiotic therapy. Five cases were temporally associated with cefaclor, one with both amoxicillin and TMP-SMZ, four with TMP-SMZ alone, and one with penicillin V alone. One case was not associated with any antibiotic exposure. All antibiotic-related cases occurred in children under age 6 years who were treated for otitis media or streptococcal pharyngitis, and most cases began 7-11 days after initiation of antibiotic. All but one of the antibiotic-related cases occurred in children who had relatively heavy lifetime antibiotic exposure. The risk of serum sickness was significantly elevated after cefaclor compared with amoxicillin, even among the most heavily exposed children (relative risk = 14.8, p = 0.01, 95% confidence interval 2.0-352.0). Most cases prompted several physician visits, but none required hospitalization.

Cost effectiveness in the choice of antibiotics for the initial treatment of otitis media in children: a decision analysis approach.

If the initial use of amoxicillin fails to cure otitis media, a family will be burdened with medical costs for a second medication, additional office visit fees and time lost from employment. For some families the initial choice of a more expensive but more effective antibiotic may be more cost effective. Using a decision analysis approach we compared the cost effectiveness of amoxicillin and cefaclor. As the amoxicillin efficacy rate decreases or as parental salaries are increased, the cost-effective advantage moves towards cefaclor. With the decision analysis method described, a practitioner can use costs and efficacy rates relevant to his or her practice to determine the most cost-effective initial antibiotic for a child with otitis media.

Therapy of acute bacterial infections with cefaclor in a pediatric population: an open assessment.

Cefaclor, a new semisynthetic cephalosporin, was given orally as a suspension to 22 infants and children with acute otitis media and or/other infections, mainly of the respiratory tract, suspected to be of bacterial origin. The drug was found to be very easily accepted by the patients, and no side effects were encountered. Most patients became asymptomatic within 48 hours. Cefaclor is active against most bacteria producing acute otitis media, including ampicillin-resistant Hemophilus influenzae, and seems to be an effective bactericidal agent in the treatment of upper respiratory tract infections. Caution is recommended when used in bacteremic infants who do not respond promptly to therapy, in view of the poor cerebrospinal fluid levels of the drug and the danger of meningitis.

Antimicrobial treatment of otitis media: penicillins, cephalosporins, sulfonamides.

Otitis media continues to be one of the most common diagnoses made in the offices of family physicians, pediatricians, and otolaryngologists. The emergence of ampicillin resistant Hemophilus influenzae as an important etiologic agent for otitis media has altered the selection of a therapeutic antimicrobial drug. This article reviews the role of the penicillins, cephalosporins, and sulfonamides in the treatment of otitis media. Amoxicillin continues to be the drug chosen for the uncultured otitis media. Backup drugs for use in unresponsive cases include trimethoprim-sulfamethoxazole, erythromycin-sulfisoxazole, and cefaclor. The cost of the drug should be a factor in the selection when efficacy is equal.

The position of the pharmaceutical industry in the development of drugs for pediatric use.

There is broad agreement that drugs to be used by children should be evaluated in children. Dosage and side effect information, in particular, cannot be reliably extrapolated from data derived from studies in adults. Few problems are encountered in obtaining adequate studies in children of drugs such as antibiotics which have a high potential for use in the pediatric age group. A large number of drugs will have limited use in children. They should be studied in children but the relative scarcity of qualified investigators, the limited patient population available for study, and ethical considerations dictate that the studies will be completed long after studies are completed in adults. These drugs should be allowed on the market before pediatric studies are completed, but there should be a commitment by the sponsor to complete the studies so that all drugs used by children will have adequate directions for use.