Impact of Rifabutin or Rifampin on Bedaquiline Safety, Tolerability, and Pharmacokinetics Assessed in a Randomized Clinical Trial with Healthy Adult Volunteers.

Bedaquiline is a diarylquinoline that specifically inhibits mycobacterial ATP synthase. Bedaquiline has been used to effectively treat tuberculosis (TB) caused by drug-susceptible and drug-resistant Mycobacterium tuberculosis Rifamycins are a cornerstone of combination drug regimens for the treatment of TB. This phase 1, open-label, randomized, controlled trial evaluated the effect of steady-state dosing of rifabutin or rifampin on the safety, tolerability, and pharmacokinetics of bedaquiline given as a single dose. Thirty-three healthy subjects were enrolled to receive a 400-mg single oral dose of bedaquiline at two time points, on study days 1 and 29. Subjects were randomly assigned to once daily oral doses of rifabutin (300 mg/day, n = 17) or rifampin (600 mg/day, n = 16) during period 2 from days 20 to 41. Serial blood sampling for bedaquiline measurement occurred on days 1 and 29 through 336 h after bedaquiline administration. The day 29 bedaquiline pharmacokinetic parameter estimates were compared to the corresponding day 1 estimates for each rifamycin group. Steady-state rifampin reduced bedaquiline AUC0-336 approximately 45%, from 47.69 h·µg/ml in period 1 to 26.33 h·µg/ml in period 2. Bedaquiline apparent clearance accelerated 24% in rifampin-treated subjects from 6.59 liters/h in period 1 to 8.19 liters/h in period 2. Steady-state rifabutin resulted in little quantitative impact on bedaquiline exposure but was associated with grade 3 and 4 adverse events before and after the day 29 bedaquiline dose. Dosage adjustments may therefore be necessary to ensure that bedaquiline plasma concentrations reach therapeutic levels safely when combining bedaquiline and rifamycins in TB treatment regimens. (This single-site, randomized, open-label, prospective study in healthy adult volunteers was registered at Clinicaltrials.gov under registration no. NCT01341184.).

A Phase 1 Pharmacokinetic and Safety Study of Extended-Duration, High-dose Cefixime for Cephalosporin-resistant Neisseria gonorrhoeae in the Pharynx.

BACKGROUND: There are no fully oral recommended treatment regimens for gonorrhea. Inadequately treated pharyngeal gonococcal infections are a likely reservoir for transmission and development of antimicrobial resistance. We sought to determine an oral cefixime dosing regimen that would theoretically treat pharyngeal infections by gonococci with minimum inhibitory concentrations 0.5 µg/mL. METHODS: We conducted an open-label, nonrandomized, phase I pharmacokinetic and safety study of cefixime in 25 healthy male and female volunteers divided into 4 dosing cohorts (cohort A, 400 mg; cohort B, 800 mg; cohort C, 1200 mg; and cohort D, 800 mg every 8 hours × 3 doses [total dose 2400 mg]) with a target serum concentration of at least 2.0 µg/mL for more than 20 hours. Cefixime concentrations from serum and pharyngeal fluid were determined with use of a validated liquid chromatography-tandem mass spectrometry assay. Safety measures included laboratories, physical examinations, and symptom diaries. RESULTS: None of the single-dose regimens attained the target concentration; however, 50% of subjects in cohort D attained the target concentration. Variation in absorption and protein binding contributed to differences in concentrations. Pharyngeal fluid concentrations were negligible. The single-dose regimens were well tolerated; the multidose regimen resulted in mild to moderate gastrointestinal symptoms in 43% of subjects. CONCLUSIONS: None of the dosing regimens achieved the target concentration. However, the proposed theoretical target was extrapolated from penicillin data; there are no empirically derived pharmacokinetic/pharmacodynamic criteria for pharyngeal gonorrhea. Under alternative cephalosporin-specific therapeutic goals, the multidose regimen may be effective, although the absence of cefixime in pharyngeal fluid is concerning. A clinical trial evaluating efficacy and defining pharmacokinetic/pharmacodynamic outcomes may be warranted.

Determination of appropriate weight-based cutoffs for empiric cefazolin dosing using data from a phase 1 pharmacokinetics and safety study of cefazolin administered for surgical prophylaxis in pediatric patients aged 10 to 12 years.

Despite over 40 years of worldwide usage, relatively few data have been published on the pharmacokinetics of cefazolin in pediatric surgical patients. The primary objectives of this study were to examine the pharmacokinetics and safety of cefazolin in children 10 to 12 years of age (inclusive) receiving 1 or 2 g of cefazolin, based on body weight. This multiple-center, open-label study enrolled pediatric patients electively scheduled for surgical procedures who required cefazolin as part of their routine clinical management. Patients weighing ≥25 to <50 kg received a 1-g dose, and patients weighing ≥50 to ≤85 kg received a 2-g dose. Postdose pharmacokinetic and safety assessments were conducted following drug administration. Cefazolin concentration-time data were analyzed by using both noncompartmental and population pharmacokinetics methods. Monte Carlo simulations were performed to identify appropriate weight-based cutoffs for the dosing of children aged 10 to 17 years of age. Twelve patients were enrolled in this study and provided the requisite pharmacokinetic data. In general, cefazolin was well tolerated. The mean cefazolin terminal elimination half-life, clearance, and area under the concentration-time curve from time zero to infinity in this population were 1.95 h, 0.804 ml/min/kg, and 607 mg · h/liter, respectively. Patients weighing 50 to 60 kg exhibited elevated cefazolin exposures. Observed pharmacokinetic parameters and simulation results indicated that a weight-based cutoff of 60 kg is predicted to provide cefazolin exposure consistent with that observed in normal, healthy adults at recommended doses for surgical prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. NCT01904357.).

A population pharmacokinetic modeling approach shows that serum penicillin G concentrations are below inhibitory concentrations by two weeks after benzathine penicillin G injection in the majority of young adults.

Serum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group A Streptococcus pyogenes (GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks.

Dosing Colistimethate Every 8 h Results in Higher Plasma Concentrations of Active Colistin Than Every 12-Hourly Dosing without Increase in Nephrotoxicity: A Phase 1 Pharmacokinetics Trial in Healthy Adult Volunteers.

Despite its use for decades, pharmacokinetic (PK) and safety studies on colistin are limited. We conducted a phase l, open-label trial to evaluate the safety and PK of multiple doses of intravenous (IV) and aerosolized colistimethate sodium (CMS) administered separately and in combination. In total, 31 healthy adults were enrolled into three cohorts of 9, 10, and 12 participants, respectively. Each cohort received increasing doses of CMS over three dosing periods as follows: Period 1 (IV only), 2.5 mg/kg every 12 h (q12h) to 3.3 mg/kg every 8 h (q8h); Period 2 (aerosolized only), 75 mg 2-4 doses, and Period 3 (combined IV aerosolized), in which was Periods 1 and 2 combined. Safety assessments, serum and lung concentrations of colistin analytes (colistin A, colistin B, CMS A, and CMS B), and kidney biomarkers were measured at specified time points. Increasing the CMS dose from 2.5 mg/kg q12h to q8h resulted in a 33% increase in serum colistin A concentrations from 3.9 µg/mL to 5.3 µg/mL-well above the accepted target of 2 µg/mL for 6 h after dosing, without evidence of nephrotoxicity. However, there was an increase in neurotoxicity, primarily perioral and lingual paresthesias, and self-limited ataxia. IV administration did not increase the lung concentrations of colistin.

Assessing time to pulmonary function benefit following antibiotic treatment of acute cystic fibrosis exacerbations.

BACKGROUND: Cystic Fibrosis (CF) is a life-shortening genetic disease in which ~80% of deaths result from loss of lung function linked to inflammation due to chronic bacterial infection (principally Pseudomonas aeruginosa). Pulmonary exacerbations (intermittent episodes during which symptoms of lung infection increase and lung function decreases) can cause substantial resource utilization, morbidity, and irreversible loss of lung function. Intravenous antibiotic treatment to reduce exacerbation symptoms is standard management practice. However, no prospective studies have identified an optimal antibiotic treatment duration and this lack of objective data has been identified as an area of concern and interest. METHODS: We have retrospectively analyzed pulmonary function response data (as forced expiratory volume in one second; FEV1) from a previous blinded controlled CF exacerbation management study of intravenous ceftazidime/tobramycin and meropenem/tobramycin in which spirometry was conducted daily to assess the time course of pulmonary function response. RESULTS: Ninety-five patients in the study received antibiotics for at least 4 days and were included in our analyses. Patients received antibiotics for an average of 12.6 days (median = 13, SD = 3.2 days), with a range of 4 to 27 days. No significant differences were observed in mean or median treatment durations as functions of either treatment group or baseline lung disease stage. Average time from initiation of antibiotic treatment to highest observed FEV1 was 8.7 days (median = 10, SD = 4.0 days), with a range of zero to 19 days. Patients were treated an average of 3.9 days beyond the day of peak FEV1 (median = 3, SD = 3.8 days), with 89 patients (93.7%) experiencing their peak FEV1 improvement within 13 days. There were no differences in mean or median times to peak FEV1 as a function of treatment group, although the magnitude of FEV1 improvement differed between groups. CONCLUSIONS: Our results suggest that antibiotic response to exacerbation as assessed by pulmonary function is essentially complete within 2 weeks of treatment initiation and relatively independent of the magnitude of pulmonary function response observed.

Development and validation of an LC-MS/MS method for the simultaneous determination of bedaquiline and rifabutin in human plasma.

This article describes the simultaneous determination of bedaquiline fumarate (TMC-207) and rifabutin in human plasma by stable isotope dilution tandem mass spectrometry. The methodology was developed for an investigation of potential drug-drug interactions of the two anti-tuberculosis drugs when given together to healthy human volunteers. Use of the two drugs in combination to treat disease caused by Mycobacterium tuberculosis is contemplated as the bacterium becomes resistant to many currently available drugs.

Effects of Rifamycin Coadministration on Bedaquiline Desmethylation in Healthy Adult Volunteers.

There is an urgent need to identify safe and effective combination treatments for multidrug-resistant (MDR) Mycobacterium tuberculosis infection (TB). Bedaquiline, a new diarylquinoline, is approved for the treatment of MDR pulmonary TB in combination with other drugs, which could include rifabutin, which is also used to treat drug-resistant TB. Both rifabutin and bedaquiline are metabolized via cytochrome P450 3A4, and rifabutin is an inducer of this enzyme. Bedaquiline is metabolized into its primary N-monodesmethyl metabolite, M2, and further desmethylated into an N-didesmethyl metabolite, M3. Both metabolites are cytotoxic and induce phospholipidosis. The effect of rifabutin on the generation and disposition of the 2 metabolites was investigated in healthy adult volunteers coadministered bedaquiline and either rifabutin or rifampin. Subjects received single oral doses (400 mg) of bedaquiline on days 1 and 29. Oral rifabutin (300 mg) or rifampin (600 mg) were given daily on days 20-41. In the rifabutin group maximum M2 concentrations (Cmax ) increased significantly (P < .001) from 47.59 to 79.53 ng/mL, and clearance slowed slightly (P = .01). This resulted in significantly (P < .001) increased overall exposure (area under the concentration-time curve [AUC0-τ ]). Peak concentrations of M3 increased approximately 3-fold with little decline thereafter. In rifampin recipients M2 Cmax doubled (48.44 to 101.52 ng/mL), but M2 clearance and time to Cmax significantly (P < .001) increased, and AUC0-∞ and mean residence time significantly decreased (P < .001). Peak M3 concentrations increased 4-fold and rapidly declined. Although both rifamycins accelerate desmethylation of bedaquiline and M2, differences in clearance resulted in sustained elevations of both metabolites during rifabutin, but not rifampin, treatment.

A randomized comparative study of levofloxacin versus amoxicillin/clavulanate for treatment of infants and young children with recurrent or persistent acute otitis media.

BACKGROUND: The need for alternative antimicrobial therapy for recurrent and persistent acute otitis media (AOM) in children has raised interest in assessing the efficacy and safety of fluoroquinolones for treatment of these infections. METHODS: In an evaluator-blinded, active-comparator, noninferiority, multicenter study, children (6 months to <5 years) were randomized 1:1 to receive levofloxacin (10 mg/kg twice daily) or amoxicillin/clavulanate (14:1; amoxicillin 45 mg/kg twice daily) for 10 days, with evaluations 4-6 days of therapy (visit 2), 2-5 days after completing therapy (visit 3), and 10-17 days after last dose (visit 4). Primary outcome was clinical cure at visit 3 based on resolution of clinical signs and symptoms of AOM. RESULTS: A total of 1650 children were randomized and 1305 were clinically evaluable at visit 3 (630 levofloxacin, 675 comparator). Clinical cure rates were 72.4% (456 of 630) in levofloxacin-treated and 69.9% (472 of 675) in amoxicillin/clavulanate-treated children. Cure rates were also similar for levofloxacin and comparator for each age group (< or =24 months: 68.9% versus 66.2%; >24 months: 76.9% versus 75.1%; respectively). Cure rates at visit 4 were 74.9% and 73.8% in levofloxacin and amoxicillin/clavulanate groups, respectively. The upper limits of the confidence intervals were less than the noninferiority margin of 10% indicating that levofloxacin treatment is noninferior to comparator treatment overall and in both infants (6 months to 2 years) and children 2-5 years. No differences between treatment groups regarding the frequency or type of adverse events were apparent. CONCLUSIONS: Levofloxacin was not inferior to amoxicillin/clavulanate for the treatment of recurrent and/or persistent AOM in infants and children.

Mycobactericidal activity of bedaquiline plus rifabutin or rifampin in ex vivo whole blood cultures of healthy volunteers: A randomized controlled trial.

BACKGROUND: Bedaquiline, an antimycobacterial agent approved for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin, an essential part of drug-sensitive tuberculosis treatment. We examined the pharmacokinetic interactions of bedaquiline plus either rifampin or rifabutin in 33 healthy volunteers. This sub-study of that trial examined the mycobactericidal activity of these drugs against intracellular Mycobacterium tuberculosis using ex vivo whole blood culture. METHODS: Subjects were randomly assigned to receive two single 400 mg doses of bedaquiline, alone, and, after a 4 week washout period, in combination with steady-state daily dosing of either rifabutin 300 mg or rifampin 600 mg. Blood samples were collected prior to dosing and at multiple time points subsequently, to measure plasma drug concentrations and bactericidal activity in ex vivo M tuberculosis-infected whole blood cultures (WBA). RESULTS: Single oral doses of bedaquiline produced readily detectable WBA ex vivo, reaching a maximal effect of -0.28 log/day, with negative values indicating bacterial killing. Plasma concentrations of 355 ng/ml were sufficient for intracellular mycobacteriostasis. Combined dosing with rifampin or rifabutin produced maximal effects of -0.91 and -0.79 log/d, respectively. However, the activity of the rifabutin combination was sustained throughout the dosing interval, thereby producing a greater cumulative or total effect. At low drug concentrations, rifabutin plus bedaquiline yielded greater mycobactericidal activity than the sum of their separate effects. Neither drug metabolites nor cellular drug accumulation could account for this observation. CONCLUSIONS: The combination of rifabutin plus bedaquiline produces sustained intracellular mycobactericidal activity that is greater than the sum of their individual effects. Further studies of the treatment-shortening potential of this combination are warranted.

Comparative effects of single-dose ceftriaxone versus three oral antibiotic regimens on stool colonization by resistant bacilli in children.

OBJECTIVE: The use of short-term intramuscular ceftriaxone for pediatric ambulatory conditions raises concerns regarding the promotion of resistance among colonizing enteric bacteria. This study was designed to assess the prevalence of stool colonization with resistant Gram-negative bacilli after single-dose ceftriaxone treatment compared with other regimens for acute otitis media. METHODS: Children age 3 months to 7 years and diagnosed with acute otitis media were randomized to receive treatment with single-dose ceftriaxone or with oral cefprozil, amoxicillin or azithromycin. Stool samples were obtained at enrollment and then 3-5 days, 10-14 days, and 28-30 days after therapy was initiated and screened for the presence of facultative Gram-negative bacilli resistant to ceftriaxone, cefprozil, amoxicillin, piperacillin, piperacillin-tazobactam and tobramycin. Mean prevalence of colonization by resistant organisms for each treatment group was compared at each time point. RESULTS: One thousand nine subjects were enrolled. The prevalence of colonization by a Gram-negative bacillus resistant to at least 1 of the screening antibiotics decreased after receipt of ceftriaxone but returned close to values measured at study entry by 30 days. A qualitatively similar pattern was noted for the 3 other regimens, but a quantitatively greater decrease in the prevalence of colonization by a resistant bacterium was noted at the 3- to 5-day and 10- to 14-day visits among azithromycin recipients (P < 0.001). Colonization by a Gram-negative bacillus resistant specifically to ceftriaxone was unusual at each study visit, regardless of treatment assignment. CONCLUSIONS: A single intramuscular dose of ceftriaxone had a similar effect on the prevalence of antibiotic-resistant Gram-negative facultative bacilli in the stool of healthy children when compared with commonly used oral agents.

Comparative study of levofloxacin in the treatment of children with community-acquired pneumonia.

BACKGROUND: Levofloxacin has established efficacy and safety in the treatment of community-acquired pneumonia (CAP) in adults, and its use as an alternative therapy for children with CAP has been proposed. OBJECTIVE: Assess the clinical efficacy and safety of levofloxacin compared with standard of care antibiotic therapy in the treatment of CAP in children aged 6 months to 16 years. METHODS: In an open-label, multicenter, noninferiority trial, children with CAP were randomized 3:1 to receive levofloxacin or comparator antimicrobial therapy (0.5 to <5 years: amoxicillin/clavulanate or ceftriaxone; > or =5 years: clarithromycin or ceftriaxone with clarithromycin or erythromycin lactobinate) for 10 days. The primary outcome was cure rates at the test-of-cure visit (10-17 days after completing treatment) as determined by symptoms, physical examination, and chest radiography. RESULTS: Seven hundred and thirty-eight children were enrolled and 539 (405 levofloxacin-treated, 134 comparator-treated) were clinically evaluable at test-of-cure visit. Clinical cure rates were 94.3% (382 of 405) in levofloxacin-treated and 94.0% (126 of 134) in comparator-treated children. Cure rates were also similar for levofloxacin and comparator for each age group (<5 years, 92.2% versus 90.8%; > or =5 years, 96.5% versus 97.1%; respectively) and for children categorized as being at higher risk for severe disease. Mycoplasma pneumoniae was the most frequently identified cause of pneumonia (230 children). Levofloxacin was as well tolerated as comparators, with similar type and incidence of adverse events. CONCLUSIONS: Levofloxacin was as well tolerated and effective as standard-of-care antibiotics for the treatment of CAP in infants and children.

Comparative safety profile of levofloxacin in 2523 children with a focus on four specific musculoskeletal disorders.

BACKGROUND: Fluoroquinolones, including levofloxacin, have not been recommended for use in children largely because studies in juvenile laboratory animals suggest there may be an increased risk of fluoroquinolone-associated cartilage lesions. A large prospective trial is needed to assess the risks associated with using levofloxacin in children. OBJECTIVE: Assess the safety and tolerability of levofloxacin therapy in children based on observations for 1 year after therapy. METHODS: Safety data were collected in children who participated in 1 of 3 efficacy trials (N = 2523) and a subset of these children who also subsequently participated in a long-term 1-year surveillance trial (N = 2233). Incidence of adverse events in children randomized to receive levofloxacin versus nonfluoroquinolone antibiotics was compared. Based on assessments by treating physicians and an independent data safety monitoring committee, events related to the musculoskeletal system were further categorized as 1 of 4 predefined musculoskeletal disorders (arthralgia, arthritis, tendinopathy, gait abnormality) considered most likely clinical correlates of fluoroquinolone-associated cartilage lesions observed in laboratory animals. RESULTS: Levofloxacin was well tolerated during and for 1 month after therapy as evidenced by similar incidence and character of adverse events compared with nonfluoroquinolone antibiotics. However, incidence of at least 1 of the 4 predefined musculoskeletal disorders (largely due to reports of arthralgia) was greater in levofloxacin-treated compared with nonfluoroquinolone-treated children at 2 months (2.1% vs. 0.9%; P = 0.04) and 12 months (3.4% vs. 1.8%; P = 0.03) after starting therapy. CONCLUSIONS: The incidence of 1 or more of the 4 predefined musculoskeletal disorders identified in nonblinded, prospective evaluations, was statistically greater in levofloxacin-treated compared with comparator-treated children.

Intravenous Zanamivir in Hospitalized Patients With Influenza.

BACKGROUND: Children with severe influenza infection may require parenteral therapy if oral or inhaled therapies are ineffective or cannot be administered. Results from a study investigating intravenous (IV) zanamivir for the treatment of hospitalized infants and children with influenza are presented. METHODS: This phase II, open-label, multicenter, single-arm study assessed the safety of investigational IV zanamivir in hospitalized children with influenza. Safety outcomes included treatment-emergent adverse events (TEAEs), clinical laboratory measurements, and vital signs. Clinical outcomes, pharmacokinetics, and virologic efficacy data were collected as key secondary outcomes. RESULTS: In total, 71 children received treatment with investigational IV zanamivir (exposure comparable to 600 mg twice daily in adults). TEAEs and serious TEAEs (STEAEs) were reported in 51 (72%) and 15 (21%) patients, respectively. The mortality rate was 7%, and median durations of hospital and ICU stays were 6 and 7.5 days, respectively. No STEAEs or deaths were considered related to IV zanamivir treatment, and no patterns of TEAEs, laboratory abnormalities, or vital signs were observed. The mean zanamivir exposures from 34 patients with normal renal function who received 12 mg/kg, 14 mg/kg, or 600 mg of IV zanamivir ranged from 64.5 to 110 hour·µg/mL. The median change from baseline in the viral load was -1.81 log10 copies per mL after 2 days of treatment. CONCLUSIONS: The safety profile of IV zanamivir was favorable, with no drug-related STEAEs reported. The majority of children experienced virologic response and clinical improvement during the treatment course. Systemic zanamivir exposures in children were consistent with adults.

The pharmacokinetics and safety of micafungin, a novel echinocandin, in premature infants.

BACKGROUND: : Candidal fungal infection rates in neonates are increasing and are a significant cause of mortality, especially in low birth weight infants. Micafungin is an echinocandin that works by inhibiting 1,3-beta-D-glucan synthase, an enzyme responsible for fungal cell wall synthesis. The objective of this study was to determine the safety and pharmacokinetics of micafungin in premature infants. METHODS: : This was a phase I, single-dose, multicenter, open-label, sequential-dose trial of intravenous micafungin investigating 3 doses (0.75 mg/kg, 1.5 mg/kg and 3.0 mg/kg) in 18 premature infants weighing >1000 g (n = 6 in each dosage group). A further 5 infants (500-1000 g) were enrolled in the 0.75 mg/kg dosage group only. RESULTS: : The mean +/- standard deviation gestational age in the >1000 g dosage group was 26.4 +/- 2.4 weeks and, on entry, patients had one or more of a variety of underlying conditions, including sepsis, pneumonia and other infections caused by Candida or other species. Micafungin pharmacokinetics in preterm infants appears linear. However, premature infants >1000 g on average displayed a shorter half-life (8 hours) and a more rapid rate of clearance (approximately 39 mL/h per kg) compared with published data in older children and adults. All doses of micafungin were well tolerated and no serious drug-related adverse events were observed. CONCLUSIONS: : Single doses of micafungin, ranging up to 3.0 mg/kg, appear well tolerated in premature infants weighing >1000 g. The drug's elimination half-life and total plasma clearance in preterm infants appear dissimilar to published values for these parameters in older children and adults. The reason(s) for this apparent difference remain to be investigated.

A Multicenter, Randomized, Observer-blinded, Active-controlled Study Evaluating the Safety and Effectiveness of Ceftaroline Compared With Ceftriaxone Plus Vancomycin in Pediatric Patients With Complicated Community-acquired Bacterial Pneumonia.

BACKGROUND: The broad-spectrum cephalosporin ceftaroline, a metabolite of the prodrug ceftaroline fosamil, has shown in vitro activity against clinical isolates from pediatric patients. METHODS: This multicenter, randomized, observer-blinded, active-controlled study (NCT01669980) assessed the safety and effectiveness of ceftaroline fosamil compared with ceftriaxone plus vancomycin in patients between 2 months and 17 years of age with complicated community-acquired bacterial pneumonia. Patients were randomized 3:1 (stratified by age cohort) to receive either ceftaroline fosamil or ceftriaxone plus vancomycin (comparator) as intravenous therapy for ≥3 days. Patients who met specific study criteria on or after Study Day 4 were permitted to switch to an oral study drug. Safety assessments were treatment-emergent adverse events, and the effectiveness of treatment was assessed by clinical and microbiologic outcomes. RESULTS: The median duration of intravenous treatment was 9.0 (range, 3.0-19.0) days in the ceftaroline fosamil group (N=30) and 7.5 (5.0-13.0) days in the comparator group (N=10). At least one treatment-emergent adverse event was experienced by 12/30 patients (40%) in the ceftaroline fosamil group and 8/10 (80%) in the comparator group; most treatment-emergent adverse events in both groups were mild to moderate in intensity. Clinical response rates in the modified intent-to-treat population were 52% (15/29 patients) in the ceftaroline fosamil group and 67% in the comparator group (6/9); clinical stability at Study Day 4 was 21% (6/29) and 22% (2/9), respectively. CONCLUSIONS: Ceftaroline fosamil was well tolerated and showed similar clinical response rates to ceftriaxone plus vancomycin in pediatric patients with complicated community-acquired bacterial pneumonia.

Pharmacokinetics of famotidine in infants.

BACKGROUND: Although famotidine pharmacokinetics are similar in adults and children older than 1 year of age, they differ in neonates owing to developmental immaturity in renal function. Little is currently known about the pharmacokinetics of famotidine in infants aged between 1 month and 1 year, a period when renal function is maturing. OBJECTIVE: To characterise the pharmacokinetics of famotidine in infants. DESIGN: This was a two-part multicentre study with both single dose (Part I, open-label) and multiple dose (Part II, randomised) arms. PATIENTS: Thirty-six infants (20 females and 16 males) who required treatment with famotidine and who had an indwelling arterial or venous catheter for reasons unrelated to the study. METHODS: Infants in Part I were administered a single dose of famotidine 0.5 mg/kg; the dose was intravenous or oral according to the judgement of the attending physician. Infants receiving 0.5 mg/kg intravenously were divided into two groups by age, and pharmacokinetic parameters in infants 0-3 months and >3 to 12 months of age were compared. Infants in Part II were randomised to one of the following treatments: 0.25 mg/kg/dose intravenously or 0.5 mg/kg/dose orally on day 1 and subsequent days, or 0.25 mg/kg/dose intravenously or 0.5 mg/kg/dose orally on day 1 followed by doses of either 0.5 mg/kg/dose intravenously or 1 mg/kg/dose orally on subsequent days. From day 2 onwards, age-adjusted dose administration regimens (once daily in infants <3 months of age and every 12 hours in infants >3 months of age) were used; the total number of famotidine doses ranged from 3 to 11 and the total number of days of dose administration ranged from two to eight. RESULTS: In infants <3 months of age, plasma and renal clearance of famotidine were decreased compared with infants >3 months of age. Pharmacokinetic parameters for the older infants (i.e. those >3 months) were similar to those previously reported for children and adults. Approximate dose-proportionality, no accumulation on multiple dosing and an estimated bioavailability similar to adult values were also observed. CONCLUSION: A short course of famotidine therapy in infants appears generally well tolerated, and the characteristics of famotidine pharmacokinetics during the first year of life are explained to a great degree by the development of renal function, the primary route of elimination for this drug.

The efficacy and safety of meropenem and tobramycin vs ceftazidime and tobramycin in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is characterized by chronic pulmonary infection with acute pulmonary exacerbations (APEs) requiring IV antibiotic treatment. We report on a blinded comparative trial of IV meropenem (40 mg/kg to 2 g q8h) or ceftazidime (5 mg/kg to 2 g q8h), each of which was administered with IV tobramycin (at a serum peak of > or = 8 microg/mL and a trough of < 2 microg/mL), as treatment for CF patients with APEs. METHODS: Patients who were > or = 5 years of age who were infected with ceftazidime-susceptible Pseudomonas aeruginosa were stratified by lung function and randomized to treatment with meropenem/tobramycin or ceftazidime/tobramycin. Patients infected with Burkholderia cepacia complex or ceftazidime-resistant P aeruginosa were assigned to receive open-label meropenem/tobramycin. Clinical response was assessed by spirometry to determine the change in percent predicted FEV1 and by a clinical acute change score (ACS). RESULTS: One hundred two patients were randomized to meropenem/tobramycin (n = 50) or ceftazidime/tobramycin (n = 52). Nineteen patients received open-label meropenem/tobramycin. FEV1 was improved at the end of treatment (EOT) with meropenem/tobramycin (mean [+/- SD] increase, 38.8 +/- 52.3%) and with ceftazidime/tobramycin (mean increase, 29.4 +/- 35.1%; p < 0.0001 vs baseline values). The proportion of patients with > or = 15% relative increase from baseline FEV1 (satisfactory response) at day 7 was 62% for the meropenem/tobramycin group and 44% for the ceftazidime/tobramycin group (p = 0.04). The median time to FEV1 response was 4 days for meropenem/tobramycin therapy vs 6 days for ceftazidime/tobramycin therapy. Similarly, FEV1 improved in the open-label group (mean increase, 12.5 +/- 25.7%; p = 0.05). ACS improved in all three groups at EOT (p < 0.0001 vs baseline values). CONCLUSIONS: Therapy with both meropenem/tobramycin and ceftazidime/tobramycin improved pulmonary and clinical status and reduced sputum bacterial burden in CF patients with APEs. A larger proportion of patients receiving meropenem/tobramycin therapy demonstrated a satisfactory FEV1 response at day 7. Resistant P aeruginosa emerged infrequently during treatment with both regimens.

Impact of amoxicillin on pneumococcal colonization compared with other therapies for acute otitis media.

BACKGROUND: This study compared the effects of 4 outpatient antibiotic regimens on colonization by penicillin-susceptible and -nonsusceptible pneumococci to assess their relative potential to promote colonization with Streptococcus pneumoniae with reduced susceptibility to penicillin. METHODS: Children presenting with acute otitis media were randomized to receive amoxicillin, cefprozil, ceftriaxone or azithromycin. Nasopharyngeal specimens were collected on days 0, 3-5, 10-14 and 28-30 and assessed for the presence of S. pneumoniae. At each visit, the proportions of penicillin-susceptible and -nonsusceptible pneumococci were compared among treatment groups. RESULTS: Among 1009 enrollees, the prevalence of colonization by S. pneumoniae at baseline was 23.5%, of which 41.1% were penicillin-nonsusceptible. Colonization by nonsusceptible pneumococci was unaltered during the observation period in all treatment groups, with no detectable differences among groups at each visit. By contrast, there was a substantial reduction in the prevalence of colonization by penicillin-susceptible organisms, most notably in subjects treated with amoxicillin. This resulted in a proportional shift toward resistant organism colonization in all groups, with this shift being significantly more pronounced among amoxicillin recipients than in the other groups at 10-12 days (P < 0.02 for each comparison with amoxicillin). CONCLUSIONS: Treatment with amoxicillin for acute otitis media resulted in a larger shift toward nonsusceptible organism colonization among those children still colonized postexposure than did treatment with 3 comparison agents. This phenomenon raises theoretical concerns that at the population level, amoxicillin produces conditions that promote the dissemination of the nonsusceptible phenotype more readily than other outpatient antibiotics. Confirmation of these results requires further study.

Levofloxacin pharmacokinetics in children.

Levofloxacin is a broad-spectrum fluoroquinolone antibiotic with activity against many pathogens that cause bacterial infections in children, including penicillin-resistant pneumococci. To provide dosing guidance for children, 3 single-dose, multicenter pharmacokinetic studies were conducted in 85 children in 5 age groups: 6 months to <2 years, 2 to <5 years, 5 to <10 years, 10 to <12 years, and 12 to 16 years. Each child received a single 7-mg/kg dose of levofloxacin (not to exceed 500 mg) intravenously or orally. Plasma and urine samples were collected through 24 hours after dose. Pharmacokinetic parameters were estimated and compared among the 5 age groups and to previously collected adult data. Levofloxacin absorption (as indicated by C(max) and t(max)) and distribution in children are not age dependent and are comparable to those in adults. Levofloxacin elimination (reflected by t1/2 and clearance), however, is age dependent. Children younger than 5 years of age clear levofloxacin nearly twice as fast (intravenous dose, 0.32+/-0.08 L/h/kg; oral dose, 0.28+/-0.05 L/h/kg) as adults and, as a result, have the total systemic exposure (area under the plasma drug concentration-time curve) approximately one half that of adults. The levofloxacin area under the plasma drug concentration-time curve (dose normalized) in children receiving a single dose of the oral liquid formulation is comparable to that in children receiving the intravenous formulation. To provide compatible levofloxacin exposures associated with clinical effectiveness and safety in adults, children > or =5 years need a daily dose of 10 mg/kg, whereas children 6 months to <5 years should receive 10 mg/kg every 12 hours.