Risk scoring tool to predict respiratory syncytial virus hospitalisation in premature infants.

BACKGROUND: The objective was to develop a risk scoring tool which predicts respiratory syncytial virus hospitalisation (RSVH) in moderate-late preterm infants (32-35 weeks' gestational age) in the Northern Hemisphere. METHODS: Risk factors for RSVH were pooled from six observational studies of infants born 32 weeks and 0 days to 35 weeks and 6 days without comorbidity from 2000 to 2014. Of 13 475 infants, 484 had RSVH in the first year of life. Logistic regression was used to identify the most predictive risk factors, based on area under the receiver operating characteristic curve (AUROC). The model was validated internally by 100-fold bootstrapping and externally with data from a seventh observational study. The model coefficients were converted into rounded multipliers, stratified into risk groups, and number needed to treat (NNT) calculated. RESULTS: The risk factors identified in the model included (i) proximity of birth to the RSV season; (ii) second-hand smoke exposure; and (iii) siblings and/or daycare. The AUROC was 0.773 (sensitivity: 68.9%; specificity: 73.0%). The mean AUROC from internal bootstrapping was 0.773. For external validation with data from Ireland, the AUROC was 0.707 using Irish coefficients and 0.681 using source model coefficients. Cut-off scores for RSVH were ≤19 for low- (1.0%), 20-45 for moderate- (3.3%), and 50-56 (9.5%) for high-risk infants. The high-risk group captured 62.0% of RSVHs within 23.6% of the total population (NNT 15.3). CONCLUSIONS: This risk scoring tool has good predictive accuracy and can improve targeting for RSVH prevention in moderate-late preterm infants.

CHD and respiratory syncytial virus: global expert exchange recommendations.

BACKGROUND: Palivizumab is the standard immunoprophylaxis against serious disease due to respiratory syncytial virus infection. Current evidence-based prophylaxis guidelines may not address certain children with CHD within specific high-risk groups or clinical/management settings. METHODS: An international steering committee of clinicians with expertise in paediatric heart disease identified key questions concerning palivizumab administration; in collaboration with an additional international expert faculty, evidence-based recommendations were formulated using a quasi-Delphi consensus methodology. RESULTS: Palivizumab prophylaxis was recommended for children with the following conditions: <2 years with unoperated haemodynamically significant CHD, who are cyanotic, who have pulmonary hypertension, or symptomatic airway abnormalities; <1 year with cardiomyopathies requiring treatment; in the 1st year of life with surgically operated CHD with haemodynamically significant residual problems or aged 1-2 years up to 6 months postoperatively; and on heart transplant waiting lists or in their 1st year after heart transplant. Unanimous consensus was not reached for use of immunoprophylaxis in children with asymptomatic CHD and other co-morbid factors such as arrhythmias, Down syndrome, or immunodeficiency, or during a nosocomial outbreak. Challenges to effective immunoprophylaxis included the following: multidisciplinary variations in identifying candidates with CHD and prophylaxis compliance; limited awareness of severe disease risks/burden; and limited knowledge of respiratory syncytial virus seasonal patterns in subtropical/tropical regions. CONCLUSION: Evidence-based immunoprophylaxis recommendations were formulated for subgroups of children with CHD, but more data are needed to guide use in tropical/subtropical countries and in children with certain co-morbidities.

Burden of Severe Respiratory Syncytial Virus Disease Among 33-35 Weeks' Gestational Age Infants Born During Multiple Respiratory Syncytial Virus Seasons.

BACKGROUND: Moderate-late preterm infants, 33-35 weeks' gestational age (wGA), are at increased risk for respiratory syncytial virus hospitalization (RSVH). The objective of this study is to quantify the burden of RSVH in moderate-late preterm infants. METHODS: A pooled analysis was conducted on RSVH from 7 prospective, observational studies in the Northern Hemisphere from 2000 to 2014. Infants' 33-35 wGA without comorbidity born during the respiratory syncytial virus season who did not receive respiratory syncytial virus immunoprophylaxis were enrolled. Data for the first confirmed RSVH during the season (+1 month) were analyzed. Incidence and hospitalization rate per 100 patient-seasons, intensive care unit admission and length of stay (LOS), oxygen support, mechanical ventilation and overall hospital LOS were assessed. RESULTS: The pooled analysis comprised 7,820 infants; 267 experienced a confirmed RSVH at a median age of 8.4 weeks. The crude pooled RSVH incidence rate was 3.41% and the rate per 100 patient-seasons was 4.52. Median hospital LOS was 5.7 days. A total of 22.2% of infants required intensive care unit admission for a median LOS of 8.3 days. A total of 70.4% received supplemental oxygen support for a median of 4.9 days, and 12.7% required mechanical ventilation for a median of 4.8 days. CONCLUSIONS: The burden of RSVH in moderate-late, 33-35 weeks' wGA preterm infants without comorbidities born during the viral season in Northern Hemisphere countries is substantial. Severe cases required prolonged and invasive supportive therapy.

Predictors of RSV LRTI Hospitalization in Infants Born at 33 to 35 Weeks Gestational Age: A Large Multinational Study (PONI).

BACKGROUND: Preterm infants are at high risk of developing respiratory syncytial virus (RSV)-associated lower respiratory tract infection (LRTI). This observational epidemiologic study evaluated RSV disease burden and risk factors for RSV-associated LRTI hospitalization in preterm infants 33 weeks+0 days to 35 weeks+6 days gestational age not receiving RSV prophylaxis. METHODS: Preterm infants ≤6 months of age during RSV season (1 October 2013-30 April 2014) were followed at 72 sites across 23 countries from September 2013-July 2014 (study period). RSV testing was performed according to local clinical practice. Factors related to RSV-associated hospitalization for LRTI were identified using multivariable logistic regression with backward selection. RESULTS: Of the 2390 evaluable infants, 204 and 127 were hospitalized for LRTI during the study period and RSV season, respectively. Among these subjects, 64/204 and 46/127, respectively, were hospitalized for confirmed RSV LRTI. Study period and RSV season normalized RSV hospitalization rates (per 100 infant years) were 4.1 and 6.1, respectively. Factors associated with an increased risk of RSV-related LRTI hospitalization in multivariable analyses were smoking of family members (P<0.0001), non-hemodynamically significant congenital heart disease diagnosis (P = 0.0077), maternal age of ≤25 years at delivery (P = 0.0009), low maternal educational level (P = 0.0426), household presence of children aged 4 to 5 years (P = 0.0038), age on 1 October ≤3 months (P = 0.0422), and presence of paternal atopy (P<0.0001). CONCLUSIONS: During the 2013-2014 RSV season across 23 countries, for preterm infants 33-35 weeks gestation ≤6 months old on 1 October not receiving RSV prophylaxis, confirmed RSV LRTI hospitalization incidence was 4.1 per 100 infant years during the study period and 6.1 per 100 infant years during the RSV season. This study enhances the findings of single-country studies of common risk factors for severe RSV infection in preterm infants and suggests that combinations of 4-6 risk factors may be used to accurately predict risk of RSV hospitalization. These findings may be useful in the identification of infants most at risk of severe RSV infection.

The Burden of Severe Respiratory Syncytial Virus Disease Among Children Younger than 1 Year in Central and Eastern Europe.

INTRODUCTION: Globally, respiratory syncytial virus (RSV) is the most common cause of serious lower respiratory tract infections (LRTIs) in young children, and is a major cause of hospital admission in children <1 year of age. The study evaluated the severity of RSV-associated LRTI disease among premature (<36 weeks gestational age (GA)) and term children <1 year of age and assessed the influence of GA on outcomes of RSV LRTI hospitalization in Central and Eastern Europe (CEE). METHODS: Retrospective cohort survey of children <1 year of age hospitalized with an LRTI during the periods of October 2009 to April 2010 or October 2010 to April 2011 in 12 CEE countries. RESULTS: Across two RSV seasons, 3474 evaluable children were hospitalized because of LRTI; 757 (21.8%) were premature and 2679 (77.1%) were term. RSV tests were positive in 1423 (42.4%) cases, of which 266 (18.7%) were premature and 1034 (72.7%) were term children. Among the RSV-positive patients, premature children had a significantly longer hospital stay (17 vs 8 days; P < 0.001), were more frequently hospitalized in the intensive care unit (ICU) (41.4% vs 12.6%) and remained in the ICU significantly longer (13 vs 6 days; P < 0.001) compared with term children. Premature children had a 3.3-fold (95% CI, 2.66-4.09) increased risk for ICU hospitalization compared with term children (P < 0.001). ICU hospitalization, prolonged hospital stay, supplemental oxygen administration and death occurred significantly more frequently among children with lower vs higher GA. CONCLUSION: RSV infection is associated with substantial morbidity in CEE among premature and term children. The attributable morbidity, however, is significantly greater among premature children compared with term children, including longer hospital stays and more frequent and longer stays in the ICU. These findings are consistent with previously published data outside of CEE, demonstrating prematurity as a significant and independent predictor for severe RSV disease. FUNDING: AbbVie Inc.

Review of the home care programmes for respiratory syncytial virus (RSV) prophylaxis in Ireland and The Netherlands.

Severe infection of infants with respiratory syncytial virus (RSV) is a leading cause of morbidity in the developed world and mortality in the developing world. Prophylaxis using palivizumab in infants at risk for severe RSV disease reduces the rate of hospitalisation in this population of children. To ensure complete prophylaxis, infants must receive monthly doses over the winter season. To improve parental convenience, the Synacare® programme was implemented in Ireland and the Netherlands. Synacare® is now a longstanding programme in which palivizumab is administered in the home setting by skilled nurses. Protocols and procedures described here illustrate the efficiency and acceptability of the home delivery service of RSV disease prophylaxis. Post-administration surveys have indicated a high level of parental satisfaction with the programme. At-home paediatric programmes like Synacare® may serve as an alternative to burdensome monthly hospital visits and may lead to enhanced clinical outcomes.

Safety and pharmacokinetics of extended use of palivizumab in Saudi Arabian infants and children.

BACKGROUND: The peak season of respiratory syncytial virus (RSV) infections in warmer climates may extend beyond the typical five-month RSV season of temperate regions. Additional monthly doses of palivizumab may be necessary in warmer regions to protect children at high risk for serious infection by the RSV. METHODS: In a Phase II, single-arm, single-center, non-comparative, open-label, prospective study conducted in Saudi Arabia, children at high risk for RSV infection received up to seven monthly injections of palivizumab (15 mg/kg) during the 2000-2001 RSV season. Key enrollment criteria were no previous exposure to palivizumab and gestational age ≤35 weeks, ≤6 months of age at enrollment, or chronic lung disease and ≤24 months of age at enrollment. We wished to assess the safety, immunogenicity, and pharmacokinetics of palivizumab as an extended seven-dose regimen. RESULTS: Of 18 enrolled patients, 17 patients received seven palivizumab injections. Seven adverse events (AEs) occurred in five patients. Bronchiolitis was the most commonly reported AE. Six serious AEs occurred in four patients. No AEs were considered related to palivizumab. Trough levels of palivizumab in serum were >40 µg/mL in most patients after the first injection and in 16/18 and 14/17 patients after the fourth and sixth injections, respectively. Except for one patient at one visit, the anti-palivizumab titer was <1:10 at all visits. CONCLUSION: These data suggest that an extended palivizumab regimen of up to seven monthly doses during the RSV season exhibited an acceptable safety profile in children at high risk for RSV infection in Saudi Arabia.

The burden of single virus and viral coinfections on severe lower respiratory tract infections among preterm infants: a prospective birth cohort study in Brazil.

BACKGROUND: Respiratory syncytial virus (RSV) is associated with severe lower respiratory tract infection (LRTI), especially in preterm infants. Other viruses, co-detected with RSV, may play a role in the severity of respiratory outcomes. METHODS: This prospective epidemiologic study of severe LRTI incidence among children born ≤35 weeks gestational age at 3 sites in Brazil (2008-2010) followed a birth cohort for 1 year post-enrollment. Nasal washes from subjects with LRTI were tested for respiratory viruses using polymerase chain reaction. The primary outcome was the incidence of severe LRTI requiring hospitalization associated with RSV infection. Secondary outcomes included identification of viruses associated with LRTI, alone or coinfections, and risk factors associated with severe LRTI. RESULTS: Among 303 subjects, 176 (58.1%) experienced LRTI. Among these subjects, 162 had samples tested using polymerase chain reaction; 27.8% (45/162) experienced severe LRTI. More subjects with severe LRTI were infected with RSV (30/45, 66.7%) than with other viruses. RSV was present in 33.1% (143/432) of LRTI events tested, 57.3% (82/143) were coinfections. RSV was the virus most frequently associated with severe LRTIs (34/56 events, 60.7%); 50% (17/34 events) single and 50% coinfections. Significantly longer hospital stays were associated with LRTI events involving RSV coinfections compared with RSV single infections (P = 0.012). Infants with severe LRTIs had significantly lower mean RSV-IgG levels at study entry compared with those with nonsevere or no LRTIs (P < 0.05). CONCLUSIONS: This study confirms the association of RSV alone or as a coinfection with severe LRTI and reinforces the importance of providing adequate prophylaxis for susceptible infants.

Safety and Effectiveness of Palivizumab in Children at High Risk of Serious Disease Due to Respiratory Syncytial Virus Infection: A Systematic Review.

INTRODUCTION: Lower respiratory tract infection (LRTI) is the leading cause of infant mortality globally in post-neonatal infants (i.e., 28-364 days of age). Respiratory syncytial virus (RSV) is the most commonly identified pathogen for infant LRTI and is the second most important cause of death in post-neonatal infants. Despite 50 years of RSV vaccine research, there is still no approved vaccine. Therefore, passive immunity with the monoclonal antibody palivizumab is the sole regulatory-approved option for the prevention of serious LRTI caused by RSV in pediatric patients at high risk of RSV disease. METHODS: We conducted a comprehensive systematic literature review of randomized controlled trials (RCTs), open-label non-comparative clinical trials, and prospective observational studies/registries, and summarized the evidence related to the safety, efficacy, and effectiveness of palivizumab. RESULTS: The efficacy of palivizumab, as measured by the relative reduction in RSV-related hospitalization rate compared with placebo ranged from 39% to 78% (P < 0.05) in the 2 pivotal RCTs. A meta-analysis of the RSV-related hospitalization rate from 5 randomized placebo-controlled trials yielded an overall odds ratio of 0.41 (95% CI, 0.31-0.55) in favor of palivizumab prophylaxis over placebo (P < 0.00001). Low rates of RSV-related hospitalizations were observed in palivizumab recipients consistently over time in more than 42,000 pediatric subjects across 7 RCTs, 4 open-label non-comparative trials, and 8 observational studies/registries conducted in 34 countries. In addition, among palivizumab-prophylaxed subjects with breakthrough RSV LRTI, rates of intensive care unit admission and mechanical ventilation from RSV hospitalization also were low and consistent across studies. With respect to safety, no differences were observed between palivizumab and placebo in the blinded RCTs. CONCLUSION: Rates of RSV hospitalizations and RSV hospitalization-related endpoints in pediatric subjects who received prophylaxis with palivizumab were low and constant over time and across RCTs, open-label non-comparative trials, and observational studies/registries.

Palivizumab use in Japanese infants and children with immunocompromised conditions.

A total of 27/28 (96%) immunocompromised Japanese children received ≥ 4 doses of palivizumab. No respiratory syncytial virus-associated hospitalizations occurred. Mean palivizumab trough concentrations were 59.0 and 91.8 µg/mL 30 days after the 1st and 4th doses, respectively. Of 28 subjects, 27 (96%) experienced ≥ 1 adverse event and 7 (25%) experienced ≥ 1 serious adverse event, none of which was considered related to palivizumab.

Three monthly doses of palivizumab are not adequate for 5-month protection: a population pharmacokinetic analysis.

Recent guidelines in British Columbia, Canada have suggested that the use of a maximum of 3 monthly doses of palivizumab 15 mg/kg intramuscularly for RSV immunoprophylaxis of high risk infants born prior to the RSV season is adequate to provide protection against severe RSV disease for a 5-month RSV season. Efficacy was established, however, with 2 large, randomized controlled clinical studies using 5 monthly doses of immunoprophylaxis. To evaluate the differences in expected palivizumab exposures between the 2 dosing regimens (3 vs 5 monthly doses across a 5-month period), we used a population pharmacokinetic (PK) model that was developed using palivizumab PK data collected from 22 clinical studies with a total of 1800 subjects. This model adequately described observed palivizumab concentrations from the different pediatric studies and was subsequently used to simulate expected palivizumab serum concentrations for 3 monthly doses compared with 5 monthly doses in children younger than 24 months with chronic lung disease of prematurity and infants younger than 6 months postnatal age who were born at ≤ 35 weeks gestational age. Results from the population PK model indicated lower serum concentrations of palivizumab during the fourth and fifth months, after an abbreviated 3-monthly-dose regimen when compared with the mean trough concentrations seen with the 5-monthly-dose regimen studied in the pivotal clinical trials in premature infants. Specifically, during the fourth and fifth months, 52% and 85%, respectively, would have levels below the lowest concentration (fifth percentile) in those receiving the 5-monthly-dose regimen. Simulations using this model did not support a 3-monthly-dose regimen to protect against severe RSV disease during the typical 5-month season.

A prospective, open-label, non-comparative study of palivizumab prophylaxis in children at high risk of serious respiratory syncytial virus disease in the Russian Federation.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections (LRTIs) in children globally. Predisposing conditions for the development of serious RSV disease include preterm infants and those with cardiopulmonary illness, including congenital heart disease (CHD) and bronchopulmonary dysplasia (BPD). No vaccine is currently approved for the prevention of RSV infection. It is recommended that children at high risk be prophylactically administered palivizumab, a monoclonal antibody that has been shown in a number of clinical studies to reduce hospitalization rates due to serious RSV infection. The objective of the current study was to determine the safety and effectiveness of palivizumab in preventing serious RSV disease in high-risk children in the Russian Federation. Children at high risk of serious RSV disease (ie, born at ≤ 35 wk gestational age and ≤ 6 mo of age, and/or aged ≤ 24 mo with BPD or hemodynamically significant CHD) were enrolled. Subjects were to receive 3 to 5 monthly injections of palivizumab 15 mg/kg (depending on the month of the initial injection) over the RSV season. The primary endpoint was RSV-related hospitalizations. Adverse events (AEs) were reported through 100 days following the final injection. RESULTS: One hundred subjects received ≥ 1 injection of palivizumab; 94 completed their dosing schedule. There were no RSV hospitalizations or deaths. Six of 7 subjects hospitalized for respiratory/cardiac conditions had an RSV test, which was negative in all cases. Three non-serious AEs (acute intermittent rhinitis and rhinitis, 1 subject; atopic dermatitis, 1 subject) were considered possibly related to palivizumab. All other AEs were mild or moderate and considered not related/probably not related to palivizumab. CONCLUSION: Palivizumab was generally well tolerated and effectively prevented serious RSV infection in a mixed population of high-risk children in the Russian Federation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01006629.

Comparison of risk factors between preterm and term infants hospitalized for severe respiratory syncytial virus in the Russian Federation.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in infants. Preterm birth, in addition to several demographic and environmental factors, increases the risk for development of severe RSV infection. The purpose of this study was to describe differences in risk factors and protective factors between preterm birth (up to 35 weeks' gestational age) and term infants hospitalized for RSV lower respiratory tract infection in the Russian Federation during the 2008-2009 RSV season. METHODS: Infants up to two years of age hospitalized for a lower respiratory tract infection in Moscow, St Petersburg, and Tomsk were tested for RSV. Patient data, including risk factors and protective factors for RSV, were captured at admission. Differences in these factors were compared between preterm and term patients. RESULTS: A total of 519 infants hospitalized for lower respiratory tract infection were included in the study. Of these, 197 infants (182 term and 15 preterm) tested positive for RSV. Of all hospitalizations, 51.7% (15/29) of preterm infants versus 37.1% (182/490) of term infants had confirmed RSV (P = 0.118). Among the RSV-positive patients, preterm infants were more likely to have a lower weight at admission (P = 0.050), be of multiple gestation (P < 0.001), have more siblings (P = 0.013), and have more siblings under the age of eight years (P < 0.007) compared with term patients. The preterm infants were less likely to be breastfed (P < 0.001) and more likely to have older mothers (P = 0.050). CONCLUSION: Compared with term infants, RSV was a more prevalent cause of hospitalization for lower respiratory tract infection in preterm infants. Of infants hospitalized for RSV, preterm infants were more likely to have additional risk factors for severe RSV. These findings suggest that preterm infants may be exposed to a combination of more strongly interrelated risk factors for severe RSV than term infants.

Epidemiology of respiratory syncytial virus in children ≤2 years of age hospitalized with lower respiratory tract infections in the Russian Federation: a prospective, multicenter study.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections among infants and young children, and is responsible for an estimated four million deaths per year globally. A monthly injection of palivizumab has been used for prophylaxis of serious RSV infections among high-risk children in 71 countries since 1998 and approval for use in the Russian Federation was obtained in February 2010. A recommendation for RSV prophylaxis in the Russian Federation would require knowledge of the prevalence and seasonality of RSV in that country. METHODS: In a prospective, multicenter, epidemiological study of the prevalence, seasonality, and peak occurrence of RSV infection, children aged ≤2 years hospitalized for lower respiratory tract infections in three regions of the Russian Federation, from September 2008 through April 2009, were screened and tested for RSV using rapid immunochromatography of nasopharyngeal lavage. For subjects who were tested positive, hospitalization data were collected. RESULTS: Of 519 children aged ≤2 years enrolled from September 11, 2008 through April 26, 2009, 197 tested positive for RSV (38.0%, 95% CI: 33.8, 42.3). The onset of the 2008-2009 RSV season in the Russian Federation occurred in late October 2008, similar to what is observed in other northern temperate zones. Peak activity occurred in early April 2009, when 62% of children enrolled tested positive for RSV. CONCLUSION: The prevalence of serious RSV infections in the Russian Federation is similar to the prevalence previously identified in other temperate zones of the northern hemisphere. The seasonality of disease shifted towards early spring, with peak activity later in the season, within a range reported in other countries. These data provide further evidence of serious RSV infection in children in the Russian Federation, as well as guidance for timing of seasonal RSV prophylaxis, especially among individuals at high risk for serious RSV infection.

Molecular characterization of Staphylococcus aureus isolates from a 2005 clinical trial of uncomplicated skin and skin structure infections.

A clinical trial of uncomplicated skin and skin structure infections (39 locations in 19 states) observed that community-associated or community-onset methicillin-resistant Staphylococcus aureus (CO-MRSA) represented 23% of all pathogens at baseline culture and 53% of 190 S. aureus isolates. CO-MRSA strains typically were Panton-Valentine leukocidin (PVL) positive (95%), contained staphylococcal cassette chromosome mec type IVa (99%), were USA300 or USA400 clones (92%), and exhibited minimal coresistances (macrolides and/or fluoroquinolones). Clinical results remained identical (89% cures) regardless of the antimicrobial used or CO-MRSA molecular patterns, PVL production, or antimicrobial susceptibility profiles.

Role for 5-day, once-daily extended-release clarithromycin in acute bacterial exacerbation of chronic bronchitis.

BACKGROUND: Clarithromycin is commonly dosed for 7 or more days in patients with acute bacterial exacerbation of chronic bronchitis (ABECB). Studies with other antibiotics have shown equivalent efficacy, reduced/similar frequency of adverse events, improved adherence and patient satisfaction, and lower treatment costs with a shorter treatment course. PATIENTS AND METHODS: The study population was derived from two multicenter, randomized, double-blind (North America)/single-blind (France) comparative trials in which outpatients at least 35 years old with a presumptive diagnosis of obstructive ABECB were randomized to receive clarithromycin extended-release (ER) 1000 mg once daily for 5 days or a comparator agent--clarithromycin immediate-release (IR) 500 mg twice daily for 7 days (in North America) or telithromycin 800 mg once daily for 5 days (in France). RESULTS: A total of 818 patients were randomized (411 to clarithromycin ER and 407 to a comparator agent). The clinical cure rate in clinically evaluable patients at the follow-up visit was 90% each for the clarithromycin ER group (318/353) and the comparator group (318/355). The patient bacteriological cure rate and the overall target pathogen eradication rate in clinically and bacteriologically evaluable patients were each 92% for the clarithromycin ER group (155/168 and 189/205, respectively) and 93% for the comparator group (147/158 and 183/197, respectively) at the follow-up visit. The study drugs were generally well tolerated, with < 2% of patients discontinuing their treatment prematurely due to a drug-related adverse event. The incidence of drug-related adverse events was 18% (73/411) in the clarithromycin ER group and 24% (97/407) in the comparator group. Clarithromycin ER-treated patients reported statistically significantly fewer episodes of abdominal pain than did patients treated with a comparator agent (0.2% vs. 1.7%, respectively; p = 0.037). This combined analysis is limited by differing blinding methods, comparator agents, and their duration of administration. Furthermore, many patients were excluded from the clinically and bacteriologically evaluable group due to lack of a pretreatment target pathogen. CONCLUSION: A once daily, 5-day clarithromycin ER regimen appears to be a suitable choice for treating patients with ABECB.

Efficacy, tolerability, and parent reported outcomes for cefdinir vs. high-dose amoxicillin/clavulanate oral suspension for acute otitis media in young children.

OBJECTIVES: To compare efficacy, tolerability, and parental satisfaction of cefdinir and high-dose amoxicillin/clavulanate oral suspensions given to young children with non-refractory acute otitis media (AOM) based on clinical endpoints and outcomes measures. RESEARCH DESIGN AND METHODS: This was an investigator-blinded, multicenter study in which 318 children 6 months through 6 years of age with a clinical diagnosis of AOM were randomized to receive 10 days of either cefdinir (14 mg/kg divided BID) or high-dose amoxicillin/clavulanate (90/6.4 mg/kg divided BID). MAIN OUTCOME MEASURES: Investigators evaluated clinical response at an end-of-therapy (EOT) office visit conducted on day 12-15. Outcomes of satisfaction, tolerability, and adherence were also assessed at that visit using an Otitis Parent Questionnaire. RESULTS: The treatment groups were similar at baseline with respect to patient demographics. At the EOT visit, for cefdinir and amoxicillin/clavulanate, respectively, intent-to-treat (ITT) clinical cure rates were 82% (129/158) and 85% (134/158) (p = 0.547; 95% confidence interval [CI] -11.7 to 5.4) and per-protocol cure rates were 82% (123/150) and 90% (129/143) (p = 0.045; 95% CI -16.4 to 0.0). This difference was driven primarily by reduced cefdinir response in patients with recurrent AOM (p = 0.010) and those younger than 24 months (p = 0.039). Comparing cefdinir with amoxicillin/clavulanate, parents more often reported significantly better ease of use (89% vs. 57%; p < 0.0001), better taste (85% vs. 39%; p < 0.0001), and better adherence (at least 95% of doses) (82% vs. 61%; p < 0.0001). Diarrhea/loose stools were more common in the amoxicillin/clavulanate group than in the cefdinir group (28% vs. 18%, respectively; p = 0.0341). One patient in the cefdinir group and eight patients in the amoxicillin/clavulanate group withdrew from the study prematurely due to at least one adverse event (p = 0.0364). Study limitations included assessment of clinical recurrence by telephone call rather than office visit, exclusion of children with refractory AOM, and no assessment of middle ear microbiology. CONCLUSIONS: Among young children with non-refractory AOM, cefdinir was as efficacious as high-dose amoxicillin/clavulanate in the ITT group, but somewhat less effective in per-protocol analysis. From the parental perspective, cefdinir was easier to administer, had a better taste, caused less diarrhea, and resulted in higher treatment adherence than high-dose amoxicillin clavulanate.

Cefdinir vs. cephalexin for mild to moderate uncomplicated skin and skin structure infections in adolescents and adults.

OBJECTIVES: To compare the efficacy and safety of cefdinir to that of cephalexin in adolescents and adults with mild to moderate uncomplicated skin and skin structure infections (USSSI). RESEARCH DESIGN AND METHODS: This was an investigator-blinded, multicenter study in which patients at least 13 years of age with USSSI were randomized to receive 10 days of cefdinir 300 mg twice daily (BID) or cephalexin 250 mg four times daily (QID). Patients were evaluated at baseline, by telephone on Days 3-5, and during office visits on Days 12-14 (end-of-therapy [EOT] visit) and Days 17-24 (test-of-cure [TOC] visit). MAIN OUTCOME MEASURES: Clinical response was evaluated at the TOC visit. Patient reported outcomes, including a usefulness questionnaire, were also assessed. RESULTS: Three hundred and ninety-one patients were treated. The treatment groups were well matched with regard to demographic characteristics and types of infection. Abscess(es) (26%), wound infection (24%), and cellulitis (21%) were the most common infections. At the TOC visit, the clinical cure rate for both treatment groups was 89% (151/170 for cefdinir and 154/174 for cephalexin) in clinically evaluable patients (95% CI for difference in cure rates [-6.7 to 7.3]). In the intent-to-treat analysis, cure rates were 83% for cefdinir vs. 82% for cephalexin. Clinical cure rates for infections caused by methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus were 93% (37/40) and 92% (35/38) for cefdinir vs. 91% (29/32) and 90% (37/41) for cephalexin (p > 0.999 comparing treatment groups for MSSA; p > 0.999 for MRSA). The usefulness questionnaire demonstrated that cefdinir was more highly rated in the mean composite score (87.4 vs. 83.6, p = 0.04), with the difference primarily due to the respondents' preference for the convenience of taking the study medication (mean score 93.5 vs. 74.1 for cephalexin, p < 0.001). The study had the following limitations: the requirement for culture at baseline likely skewed the enrollment of patients towards those with abscesses; the results of culture in patients with USSSIs are often nonspecific; in some patients entering the study with a diagnosis of cellulitis, the cellulitis was associated with an abscess; and, incision and drainage (I&D), spontaneous drainage, and needle aspiration are likely to have contributed to clinical response for purulent infections, and in particular MRSA-associated infections. Both study drugs were well tolerated. The most common treatment-related adverse events were diarrhea (10% cefdinir, 4% cephalexin, p = 0.017), nausea (3% and 6%, respectively, p = 0.203), and vaginal mycosis (3% and 6% of females, respectively, p = 0.500). CONCLUSIONS: This study demonstrated that empiric coverage of USSSIs with cephalosporin therapy remains an appropriate clinical strategy. MRSA infections responded well in both arms of the study, suggesting that the choice of a cephalosporin did not adversely affect patient outcome. However, cephalosporins do not have accepted, clinically relevant in vitro activity against MRSA. Hence, the clinical response rates seen in this study against MRSA infections must be interpreted with caution. Cefdinir was more highly rated than cephalexin in a composite usefulness assessment.

Comparative efficacy of once daily, 5-day short-course therapy with clarithromycin extended-release versus twice daily, 7-day therapy with clarithromycin immediate-release in acute bacterial exacerbation of chronic bronchitis.

OBJECTIVE: The objective of this study was to compare the efficacy, tolerability, and safety of two clarithromycin regimens, extended-release (ER) 1000 mg once daily for 5 days and immediate-release (IR) 500 mg twice daily for 7 days, in the treatment of acute bacterial exacerbation of chronic bronchitis (ABECB). PATIENTS AND METHODS: This was a double-blind, randomized, parallel-group, multicenter study of ambulatory patients at least 40 years old with a presumptive diagnosis of ABECB, purulent sputum, and documented evidence of chronic obstructive pulmonary disease (COPD), including forced expiratory volume in one second (FEV(1)) < 70% of predicted value. Clinical cure, bacteriological cure, and target pathogen eradication rates were determined at a test-of-cure visit (study days 14-40). Safety was assessed based on the incidence of study drug-related adverse events. RESULTS: A total of 485 patients were randomized (240 to ER and 245 to IR). Clinical cure rates were similar for evaluable patients treated with ER (84%, 157/187) and those treated with IR (84%, 172/204) (95% CI -7.9, 7.2). The bacteriological cure rates were 87% (82/94) and 89% (91/102), and the overall target pathogen eradication rates were 88% (107/122) and 89% (117/131) for the respective treatment groups. The incidence of adverse events was 13% (31/240) in the ER group and 18% (45/245) in the IR group. The rate of gastrointestinal adverse events was lower with ER (8%, 19/240) compared to IR (11%, 26/245). Clarithromycin ER-treated patients reported statistically significantly fewer adverse events due to abnormal taste than did clarithromycin IR-treated patients (3% and 8%, respectively, p = 0.012). CONCLUSION: Both once-daily, 5-day, short-course therapy with clarithromycin ER and 7-day, twice-daily therapy with clarithromycin IR were effective in resolving clinical signs/symptoms of ABECB and eradicating the causative pathogens, with no statistically significant difference in clinical cure rate between the treatment groups. Clarithromycin ER was better tolerated, causing fewer gastrointestinal adverse events and statistically significantly fewer reports of abnormal taste as compared with clarithromycin IR.

A pooled analysis of seven randomized crossover studies of the palatability of cefdinir oral suspension versus amoxicillin/clavulanate potassium, cefprozil, azithromycin, and amoxicillin in children aged 4 to 8 years.

OBJECTIVE: This analysis of the results of 7 trials compared the taste and smell acceptability scores of cefdinir oral suspension and 4 other pediatric antibiotic oral suspensions--amoxicillin/clavulanate potassium, cefprozil, azithromycin, or generic amoxicillin--using a visual smile-face scale. METHODS: Data from 7 randomized, single-blind, cross-over trials were pooled and analyzed. In each study, children aged 4 to 8 years were asked to taste and smell 2 different antibiotic suspensions and assign preference using a visual smile-face scale. Ratings were converted to a numeric score ranging from 5 (really good) to 1 (really bad). RESULTS: A total of 1011 healthy subjects were randomly assigned to 1 of 2 treatment-order groups; 965 were evaluable for the taste and smell analyses. Baseline demographics of evaluable subjects were similar among test groups. Approximately even proportions of participants were female or male (50.1 % vs 49.9%), most (84.1%) were white, and slightly more participants were aged 7 or 8 years rather than younger (age 4 years, 16.0%; age 5 years, 17.4%; age 6 years, 18.7%; age 7 years, 23.2%; age 8 years, 24.8%). Of the 965 children who tasted both antibiotic suspensions and determined their preference, 798 (82.7%) rated the taste of cefdinir as really good or good (the highest possible ratings); 712 (73.8%) assigned the same ratings to amoxicillin/clavulanate potassium, cefprozil, azithromycin, or generic amoxicillin (P < or = 0.001). With regard to smell, 671 (69.5%) rated the smell of cefdinir as really good or good; 636 (65.9%) assigned these same ratings to the comparator agents (P = NS). CONCLUSION: In this pooled analysis of data from 7 randomized, single-blind, crossover trials, children between the ages of 4 and 8 years preferred the taste of cefdinir oral suspension to that of other pediatric antibiotic suspensions. Based on smile-face scores, subjects found the smell of cefdinir oral suspension to be at least as good as that of the comparators.