Management of otitis media with effusion in young children.

OBJECTIVE: To summarize and critique the Agency for Health Care Policy and Research (AHCPR) Clinical Practice Guideline for the management of otitis media with effusion (OME) in children. DATA SOURCES: The AHCPR Clinical Practice Guideline, Otitis Media with Effusion in Young Children; the Quick Reference Guide for Clinicians, Managing Otitis Media with Effusion in Young Children; and the Parent Guide, Middle Ear Fluid in Young Children, were the primary data sources. The AHCPR developed the Guideline based on a comprehensive literature review from multiple bibliographic databases, including the National Library of Medicine. Data were also collected during open hearings and from unpublished sources derived from a call in the Federal Register. Additional citations from the biomedical literature were used for supporting evidence. STUDY SELECTION: Peer-reviewed reports of controlled, randomized studies were preferred, but other study designs were considered. Over 3000 abstracts were identified, of which 378 articles were used for data extraction, and an additional 100 articles were included from bibliography review and panel recommendations. An expert panel reviewed the data and incorporated clinical expertise into the development of consensus statements. DATA EXTRACTION: Data were extracted to apply to a base case with OME to narrow the scope of the Guideline. The base case was defined as a child who is 1-3 years old, is otherwise healthy, and has no underlying craniofacial, neurologic, or sensory conditions. Multiple meta-analyses were done to help the panel come to conclusions on several issues. DATA SYNTHESIS: The Guideline documents carefully outlined treatment algorithms for the management of OME in otherwise healthy children. The main areas that need to be further clarified are the role of more aggressive identification of causative pathogens, when antimicrobial therapy should be initiated, and which antimicrobial agents are preferred for the treatment of OME. There are many vague areas in the Guideline that allow for multiple interpretations. Data regarding the use of corticosteroids were influenced heavily by the expert opinion of the panel rather than the literature-based evidence and potential cost implications. The Guideline provided specific recommendations for the surgical management of OME. Confounding patient factors that would affect decisions on management of OME, such as underlying disease states and physical or mental abnormalities, were not addressed in the Guideline. CONCLUSIONS: The documents were well organized and provide detailed explanation of the recommendations. The Guideline provides specific criteria for the surgical management of OME, but is vague in its recommendations on the medical management of OME with antibiotics, corticosteroids, and the use of invasive tympanocentesis in the evaluation of OME in otherwise healthy children.

Multiple-dose pharmacokinetics of pentoxifylline and its metabolites during renal insufficiency.

OBJECTIVE: To characterize pentoxifylline (PTF) and metabolite disposition after multiple oral doses given two and three times a day to patients with renal dysfunction. DESIGN: An open-label, randomized, crossover, parallel group design. SETTING: Community-based clinical research center. PATIENT POPULATIONS: Subjects with renal function stratified based on 24-hour urinary creatine clearance (Clcr): group I = Clcr > 80 mL/min (n = 9); group II = Clcr 30-80 mL/min (n = 6); and group III = Clcr < 30 mL/min (n = 10). METHODS: PTF 400 mg bid or tid was administered on days 1-7 and 400 mg bid or tid was given on days 14-20 with a 1-week washout. Timed blood samples were taken on days 1, 7, and 20. Blood samples were analyzed for PTF and its metabolites (M-I, M-IV, M-V) by gas-liquid chromatography. MAIN OUTCOME MEASURES: Maximum plasma concentrations (Cmax), time to maximum concentration (tmax), average steady-state plasma concentration (CavgSS), and area under the plasma concentration-time curve at steady-state (AUCSS) were determined by visual and model independent methods. ANOVA, paired t-test, and linear regression were used with significance level set at p < 0.05. RESULTS: The ratio of PTF AUCSS (tid):AUCSS (bid) and M-I AUCSS (bid and tid) were not significantly different between the groups. Significant differences were found in M-IV and M-V Cmax, AUCSS, CavgSS, and AUCSS ratios (M-IV:PTF and M-V:PTF) between renal function groups (p < 0.05 for all). A change in dosage regimen from tid to bid resulted in significant changes in M-IV and M-V CavgSS for subjects with normal renal function and in those with moderate dysfunction, although not in subjects with severe renal dysfunction. CONCLUSIONS: Renal dysfunction did not cause significant accumulations of PTF or M-I after multiple bid and tid dosing, however, M-IV and M-V had significant accumulation in patients with renal impairment. Dosage reduction to 400 mg bid for patients with moderate renal impairment and 200-400 mg/d for severe renal impairment, as well as close clinical monitoring, seem prudent until the complex pharmacologic interactions of PTF and its metabolites can be further delineated.

Prospective evaluation of ten methods for estimating creatinine clearance in children with varying degrees of renal dysfunction.

The objective of this study was to evaluate ten methods for calculating creatinine clearance (Clcr) in children with renal dysfunction. The design was a prospective, comparative study using 24-h urinary Clcr as the criterion standard. Twenty-two children (age 7-16 years old) were studied. Urinary Clcr ranged from 0 to 161 ml/min/1.73 m2. Calculated Clcr and 24-h urinary Clcr were evaluated statistically. Linear regression analysis, nominal frequency, and mean relative error were used to rank the methods. Children were stratified based on gender and renal function. None of the methods correlated well when Clcr > 100 ml/min/1.73 m2. Predictive performance deteriorated as Clcr decreased. Simple methods using height and serum creatinine were best. Clcr (ml/min/1.73 m2) = (0.52 x height (cm)/serum creatinine)--3.6 was the best equation for estimating Clcr in our patient population consisting of children over 7 years of age with stable serum creatinine.

Adequacy of recommended aminophylline loading doses in children.

The adequacy of a loading dose of aminophylline 6 mg/kg i.v. in hospitalized pediatric patients with reactive airway disease was studied. Children six months to 14 years of age were studied to determine their serum theophylline concentrations after they were given an aminophylline loading dose of 5-7 mg/kg i.v. and to see whether they had to receive additional bolus doses. Bolus doses were infused over 20-30 minutes and were followed by a continuous infusion. Additional bolus doses were administered if the patient's serum theophylline concentration and clinical condition indicated they were necessary. Data from two separate phases of the study were combined for analysis. Phase 1 was designed for estimating population pharmacokinetic values. Some 72% of the 64 patients studied had subtherapeutic serum theophylline concentrations (< 10 mg/L) within 5.5 hours of the loading dose, and 78% required at least one additional bolus dose. Males had significantly lower serum theophylline concentrations than females; of the patients with subtherapeutic concentrations, 67% were males. Patients five years of age or younger were more likely than older children to have subtherapeutic theophylline concentrations. A 6-mg/kg loading dose of i.v. aminophylline did not produce adequate serum theophylline concentrations or eliminate the need for a second bolus dose in most pediatric patients with acute exacerbations of asthma.

Cefpodoxime proxetil: a new, broad-spectrum, oral cephalosporin.

OBJECTIVE: To discuss the chemistry, pharmacokinetics, spectrum of activity, clinical trials, adverse effects, drug interactions, and dosage guidelines of cefpodoxime proxetil. DATA SOURCES: Literature was identified through a MEDLINE search from 1988 to the present and from review of bibliographies in that literature. STUDY SELECTION: Data were limited to comparative trials published in the English literature. Although many studies were conducted in Japan, the results often were available only in Japanese or partly in English. As these studies could not be completely evaluated, they are not included in this review. DATA SYNTHESIS: Cefpodoxime exhibits good activity against many gram-positive and gram-negative organisms. In clinical trials, cefpodoxime was similar in both clinical and bacteriologic efficacy to amoxicillin, cefaclor, amoxicillin/clavulanate, and penicillin in the treatment of respiratory and urinary tract infections. It also appeared effective in the treatment of skin and soft tissue infections, although no comparative trials have been performed. Cefpodoxime is well tolerated by children and is effective in the treatment of otitis media and pharyngitis. It has a similar adverse effect profile to that of other penicillins and cephalosporins, with gastrointestinal effects being most common. CONCLUSIONS: Cefpodoxime demonstrates good in vitro activity against pathogens frequently associated with respiratory tract, urinary tract, and skin and tissue infections. It has not demonstrated greater efficacy than the other antibiotics to which it has been compared. The available published clinical trials are fraught with methodologic, statistical, and evaluative flaws. Thus, further trials comparing cefpodoxime with established treatments, as well as the newer cephalosporins, are needed before its place in therapy can be established.

Acute pulmonary edema after polyethylene glycol intestinal lavage in a child.

OBJECTIVE: To report the case of an eight-year-old girl, without preexisting cardiac or renal disease, who developed acute pulmonary edema and severe respiratory distress after balanced electrolyte with polyethylene glycol (BE-PEG) intestinal lavage. CASE SUMMARY: During the nasogastric infusion of a one-liter dose of BE-PEG (OCL, Abbott), the patient experienced abdominal discomfort, gagging, vomiting and coughing. After the nasogastric infusion, the patient again had emesis, developed tachypnea, intercostal retractions, and acute respiratory distress. She received oxygen and subsequently required intubation and ventilatory support. Physical examination revealed pulmonary congestion bilaterally but no signs of cardiac failure or sepsis. Chest X-ray revealed bilateral pulmonary edema. Ventilatory support was continued for 36 hours and the patient was extubated after two days. DISCUSSION: Enteral BE-PEG may have caused acute pulmonary edema secondary to aspiration or systemic fluid overload. Although the exact cause remains unknown, the close temporal onset of pulmonary edema after BE-PEG administration in an otherwise healthy child suggests a causal relationship. CONCLUSIONS: This case should alter clinicians to the potential for significant morbidity with BE-PEG solutions, particularly if used in outpatient settings. Patients who receive BE-PEG should be closely observed and monitored for potential aspiration, excessive infusion rates, and gastrointestinal symptoms to optimize efficacy and reduce morbidity.

In vitro evaluation of a continuous-sampling device for pharmacokinetic parameter estimation.

Using an in vitro pharmacokinetic model, area under the curve (AUC) estimates from an osmotic continuous-withdrawal device were compared to AUC estimates by a conventional trapezoidal method. Ten experiments were done under two different conditions: (a) half-life of 1 h (n = 5) and (b) half-life of 2 h (n = 5). Sampling was done for 6 and 12 h, respectively. The AUC estimates from the two methods were highly correlated (r = 0.948, p < 0.0001). The mean coefficient of variation was 9.5% (n = 10), and mean AUC values were not statistically different by analysis of variance (p = 0.4). The sampling device sampled at 0.121 +/- 0.011 ml/h; the mean volume was 0.79 +/- 0.03 and 1.34 +/- 0.02 ml over 6 and 12 h, respectively. Continuous sampling provided a reasonable estimation of AUC, required only one analytical sample, and sampled at a consistent zero-order rate.

The relation between type of renal disease and renal drug clearance in children.

It is generally assumed that the renal clearance of drugs in patients with renal impairment are affected to a similar extent regardless of the type of renal disease (intact nephron hypothesis). We have studied the effect of underlying renal disease on the pharmacokinetics of cefotaxime and desacetylcefotaxime in two groups of children (ages 7 to 16 y) with varying degrees of renal dysfunction. Patients in group 1 (n = 5) had intrinsic renal disease and those in group 2 (n = 5) had extrinsic renal disease, as identified by the primary renal lesion. After a single intravenous dose of cefotaxime timed blood and urine samples were collected for 24 h; cefotaxime and desacetylcefotaxime were measured by HPLC. There were no significant differences between the groups in age, body surface area, urine output, creatinine clearance, total body clearance, nonrenal clearance, renal clearance, and volume of distribution at steady state of cefotaxime, and renal clearance of desacetylcefotaxime. However, the renal clearance: creatinine clearance (CLR:CLCR) ratios for both cefotaxime [1.34 in group 1 vs. 0.51 in group 2] and desacetylcefotaxime [1.58 in group 1 vs. 0.75 in group 2] were statistically significant between the two groups. Group 1 patients had an average CLR:CLCR ratio greater than 1 for both the parent compound and the metabolite, suggesting that net tubular secretion was still intact, despite a diminished glomerular filtration rate (CLCR = 24 ml.min-1.73 m-2).(ABSTRACT TRUNCATED AT 250 WORDS)

Overestimation of serum vancomycin concentrations using a fluorescence polarization immunoassay (Tdx) in preterm neonates.

Serum vancomycin concentrations determined by fluorescence polarization immunoassay (FPIA) with a specific high-performance liquid chromatography (HPLC) method in preterm neonates were compared. Preterm neonates (< 38 weeks gestational age) requiring vancomycin therapy and serum vancomycin concentration monitoring were enrolled. Peak serum vancomycin concentration samples were collected and independently analyzed by FPIA and HPLC. Multivariate and stratified data analysis was done with mean absolute error and mean percent error as dependent variables and independent variables as postconceptional age, postnatal age, gestational age, weight, and duration of therapy to characterize the findings. A total of 15 paired vancomycin concentrations were analyzed from neonates with a mean gestational age of 30 +/- 4 weeks. The mean percentage error of FPIA versus HPLC vancomycin concentrations was 18.1 +/- 11.1% and the mean absolute error was 3.7 +/- 2.0 mg/l. Postconceptional age, weight, and time from initiation of therapy to sample collection were independent variables which best characterized the overestimation of FPIA vancomycin concentrations. The FPIA vancomycin assay method overestimated actual vancomycin concentrations in preterm neonates. Preterm neonates less than 30 weeks postconceptional age, less than 1,200 g body weight, and duration of therapy greater than 48 h prior to concentration determination had the greatest difference in FPIA and HPLC results. Significant error in pharmacokinetic parameter estimations and dosage adjustments is possible when vancomycin concentrations are determined by FPIA.

Treatment options for the pharmacological therapy of neonatal meningitis.

Neonatal bacterial meningitis has a relatively low incidence in developed countries, but continues to cause morbidity and mortality despite advances in antimicrobial therapy. Bacterial pathogens commonly associated with neonatal meningitis include Group B streptococci, Escherichia coli K1 and other coliforms, Listeria monocytogenes and staphylococci. As it can be difficult to differentiate meningitis from septicaemia in neonates, empirical antibiotic therapy should be effective for both. Selection of an empirical antibiotic regimen should be based on: (a) bacterial prevalence and susceptibility; (b) drug characteristics; (c) postnatal age at the onset of disease; and (d) patient-specific factors. A penicillin in combination with an aminoglycoside or cefotaxime is commonly used in empirical therapies. The increased risk of staphylococcal infection in older neonates requires consideration of an antistaphylococcal antibiotic in the empirical therapy regimen. Once a causative organism has been identified, antimicrobial therapy should be directed towards that pathogen. Duration of therapy remains empirical, but should be at least 7 days for documented bacterial meningitis. Viral meningitis continues to have a high mortality despite the availability of antiviral agents. Adjunctive therapies may further reduce the morbidity and mortality of meningitis. While most of these therapeutic options have not been investigated in neonates, they may prove to be of benefit in the future. Anti-inflammatory agents, such as glucocorticoids, nonsteroidal anti-inflammatory agents and immunoglobulin, may modulate the inflammatory response of a meningeal infection. Other possible therapies in neonatal meningitis include cerebral blood flow modulators and disease prevention with maternal vaccines and perinatal antibiotics. Practical aspects of drug therapy such as route of administration and serum drug concentration monitoring can improve both drug therapy and patient outcome. While antibiotics have greatly improved the treatment outcome of neonatal meningitis, it is clear that additional intervention will be required to increase cure rates and reduce sequelae.

Cefotaxime and metabolite disposition in two pediatric continuous ambulatory peritoneal dialysis patients.

OBJECTIVE: To characterize the pharmacokinetics of cefotaxime and desacetylcefotaxime in pediatric patients undergoing continuous ambulatory peritoneal dialysis (CAPD) after intraperitoneal administration of cefotaxime. DESIGN: Case series. SETTING: Ambulatory children from Children's Hospital nephrology clinic, Columbus, Ohio. PATIENT POPULATION: Two adolescents without peritonitis. METHODS: A single intraperitoneal dose of cefotaxime 500 mg per 1 L dianeal was given during CAPD. Cefotaxime and desacetyl-cefotaxime were measured in plasma, urine, and dialysate by HPLC. RESULTS: Maximum plasma concentration (Cmax) of cefotaxime was 11.94 and 13.08 mg/L and that of desacetylcefotaxime 5.73 and 5.33 mg/L. Time to reach maximum concentration (Tmax) of cefotaxime was 2.22 and 4.08 h, and that of desacetylcefotaxime was 5.33 and 5.73 h after instillation of the intraperitoneal cefotaxime dose. Systemic absorption of cefotaxime was 56.6 and 64.8 percent. Total clearance of cefotaxime was 62 and 79 mL/min/1.73 m2. Nonrenal clearance accounted for nearly 95 percent; renal and CAPD clearance contributed approximately 5 percent of the total clearance. Renal and CAPD clearance measurements of desacetylcefotaxime were similar to those for cefotaxime. Cefotaxime half-life was 1.83 and 2.49 h and desacetylcefotaxime half-life was 8.14 and 11.0 h. CONCLUSIONS: Cefotaxime was well absorbed and therapeutic serum concentrations were achieved after intraperitoneal administration. Renal and CAPD clearances for cefotaxime and desacetylcefotaxime were low. Cefotaxime nonrenal clearance was unaffected. Further studies are needed to establish appropriate intraperitoneal dosing guidelines of cefotaxime in pediatric CAPD patients.

Pharmacokinetics of cefotaxime and its active metabolite in children with renal dysfunction.

We studied cefotaxime (CTX) and desacetylcefotaxime (dCTX) pharmacokinetics in 19 children (ages, 7 to 16 years) with various degrees of renal function. The patients were stratified into three groups according to 24-h urinary creatinine clearance (CLCR) values: group I, CLCR greater than 80 ml/min/1.73 m2 (n = 7); group II, CLCR from 30 to 80 ml/min/1.73 m2 (n = 6); and group III, CLCR less than 30 ml/min/1.73 m2 (n = 6). A single 50-mg/kg dose of CTX was given intravenously to each patient after which blood and urine samples were collected and analyzed for CTX and dCTX by high-performance liquid chromatography. Safety was assessed by pre- and poststudy blood chemistries and urinalysis. The mean values for total body clearance of CTX for groups I, II, and III were 158.1 +/- 38.8, 118.3 +/- 50.8, and 84.8 +/- 11.7 ml/min/1.73 m2, respectively (P less than 0.01). Renal clearance also decreased across groups, I, II, and III, with values of 77.5 +/- 20.2, 41.3 +/- 18.5, and 11.4 +/- 7.7 ml/min/1.73 m2 respectively (P less than 0.0001). Both the CTX fraction nonrenally cleared and elimination half-life increased with decreasing renal function. The CTX volume of distribution at steady state was not affected by renal disease. The renal clearance values of dCTX were 146.4 +/- 71.4, 64.5 +/- 32.1, and 14.4 +/- 8.7 ml/min/1.73 m2 for groups I, II, and III, respectively (P less than 0.0004). Elimination half-life values were 2.04 +/- 0.39, 3.87 +/- 1.93, and 6.19 +/- 3.22 h for the respective groups (P less than 0.006). Both the maximum concentration of dCTX in plasma and time to reach the maximum concentration of dCTX in plasma were increased with decreased CLCR. The results of this study indicate that dosage adjustment may be necessary for CTX in children with renal dysfunction. On the basis of the pharmacokinetics and antimicrobial activities of the parent drug and its metabolite, dosage reductions of 25 to 50% in children with moderate renal impairment (CLCR from 30 to 80 ml/min/1.73 m2) and 50 to 75% in children with severe renal impairment (CLCR < 30 ml/min/1.73 m2) are recommended.

Clinical pharmacokinetics of antibacterial drugs in neonates.

Neonatal patients are surviving longer due to the rapid advances in medical knowledge and technology. Our understanding of the developmental physiology of both preterm and full term neonates has also increased. It is now apparent that differences in body composition and organ function significantly affect the pharmacokinetics of antibacterial drugs in neonates, and dosage modifications are required to optimise antimicrobial therapy. The penicillins and cephalosporins are frequently used in neonates. Although ampicillin has replaced benzylpenicillin (penicillin G) for empirical treatment of neonatal sepsis, many of the other penicillins may be used in neonates for the management of various infections. Increased volume of distribution (Vd) and decreased total body clearance (CL) affect the disposition of penicillins and cephalosporins. Decreased renal clearance (CLR) due to decreased glomerular filtration and tubular secretion is responsible for the decreased CL for most of the beta-lactams. Aminoglycoside Vd is affected by the increased total body water content and extracellular fluid volume of neonates. The increased Vd, in part, accounts for the extended elimination half-life (t1/2) observed in neonates. Aminoglycoside CL is dependent on renal glomerular filtration which is markedly decreased in neonates, especially those preterm. These drugs appear to be less nephrotoxic and ototoxic in neonates than in older patients, and the role of serum concentration monitoring should be limited to specific neonatal patients. Other antibiotics such as vancomycin, teicoplanin, chloramphenicol, rifampicin, erythromycin, clindamycin, metronidazole and cotrimoxazole (trimethoprim plus sulfamethoxazole) may be used in certain clinical situations. The emergence of staphylococcal resistance to penicillins has increased the need for vancomycin. With the exceptions of vancomycin and chloramphenicol, the efficacy and safety of these other agents in neonates have not been established. The need for serum vancomycin concentration monitoring may be limited, as with aminoglycosides, while safety concerns warrant the routine monitoring of serum chloramphenicol concentrations in neonates. Dosing guidelines are provided, based on the pharmacokinetics of the drugs and previously published recommendations. These dosing guidelines are intended for initial therapy, and close therapeutic monitoring is recommended for maintenance dose requirements to optimise patient outcome. There has been an enormous increase in our knowledge of neonatal physiology and drug disposition. Fortunately, many of the antibacterial drugs used in neonates (e.g. penicillins and cephalosporins) are relatively safe. It will be important to evaluate all newly developed antibiotics in neonates to assure their maximum efficacy and safety.

Stability of cefotaxime in two peritoneal dialysis solutions.

The stability of cefotaxime sodium at room and body temperatures in peritoneal dialysis solutions containing 1.5% or 4.25% dextrose was determined. Cefotaxime sodium 2 g was added to three 2-L bags of dialysis solution containing 1.5% dextrose, and cefotaxime sodium 500 mg was added to three 500-mL bags of dialysis solution containing 4.25% dextrose. The bags were stored at 25 or 37 degrees C Samples from bags stored at 25 degrees C were drawn aseptically at 0, 12, 24, 48, and 72 hours, and samples from bags stored at 37 degrees C were drawn at 0, 6, 12, and 24 hours. The pH of each sample was determined, and the cefotaxime concentration was measured by a stability-indicating high-performance liquid chromatographic method. At 37 degrees C the initial mean cefotaxime concentration declined to 97.9% at six hours, 89.1% at 12 hours, and 68.8% at 24 hours in the 1.5% dextrose solution; the mean percentages remaining in the solution containing 4.25% dextrose were 96.4%, 86.1%, and 71.0% at 6, 12, and 24 hours, respectively. At 25 degrees C the initial cefotaxime concentration declined to 92.4%, 84.4%, and 74.2% at 24, 48, and 72 hours, respectively, in 1.5% dextrose solution and to 92.0%, 84.3%, and 80.3% at 24, 48, and 72 hours, respectively, in 4.25% dextrose solution. In both solutions, cefotaxime concentration decreased by more than 10% at and after 12 hours at 37 degrees C and between 24 and 48 hours at 25 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical use of trimethoprim/sulfamethoxazole during renal dysfunction.

This article reviews the pharmacokinetics, clinical use, and adverse effects of trimethoprim/sulfamethoxazole (TMP/SMX) in renally impaired patients. Renal dysfunction changes the pharmacokinetics of both component drugs. TMP and SMX disposition are not significantly altered until creatinine clearance is less than 30 mL/min, when SMX metabolites and TMP accumulate and may lead to toxicity. Renal dysfunction, however, does not preclude the use of TMP/SMX to treat susceptible infections, even when creatinine clearance is less than 15 mL/min. Adverse effects may occur more frequently in renally impaired patients but are not clearly related to increased serum concentrations of either drug. Guidelines for appropriate dosing and monitoring of TMP/SMX therapy in these patients are presented.