Pegasparaginase silent inactivation during therapy for NK/T cell lymphoma.

Natural Killer/T cell (NK/T cell) lymphoma is a rare, yet aggressive T cell lymphoma, which often displays resistance to traditional chemotherapies. Asparagainse (ASNase), through its unique mechanism of action, has become a vital component in the treatment of NK/T cell lymphoma. However, because ASNase is of bacterial origin, antibody formation can render the therapy ineffective, even in the absence of clinical hypersensitivity, which has been coined 'silent inactivation.' While the phenomenon of silent inactivation of PEG-ASNase is well documented in the treatment of ALL, it has not been described in NK/T cell lymphoma patients. Herein, we report a case series of six patients treated for NK/T cell lymphoma with PEG-ASNase who subsequently developed silent inactivation identified using therapeutic drug monitoring (TDM). The goal of this manuscript is to alert clinicians of this phenomenon, and review the importance of TDM in NK/T cell lymphoma patients receiving ASNase.

Comparative effectiveness of pegfilgrastim, filgrastim, and sargramostim prophylaxis for neutropenia-related hospitalization: two US retrospective claims analyses.

OBJECTIVE: Few studies have compared the effectiveness of filgrastim (FIL), pegfilgrastim (PEG), and sargramostim (SAR) to reduce the risk of febrile neutropenia (FN) associated with myelosuppressive chemotherapy (M-CT). Two large commercial database analyses were separately conducted to examine the incidence of neutropenia-related and all-cause hospitalizations associated with FIL, PEG, and SAR prophylaxis for patients receiving M-CT for non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, or solid tumors. METHODS: Separate retrospective US claims database analyses utilized patient data from January 1, 2004 to April 30, 2010 using the HealthCore Integrated Research Database (HIRD(SM)) and January 1, 2001 to August 31, 2009 using OptumInsight's (formerly Ingenix) database. Patients were ≥18 years old and treated with M-CT for NHL, Hodgkin lymphoma, and solid tumors. All identified M-CT cycles with prophylactic (first 5 days of cycle) FIL, PEG, or SAR were included in the analysis. Patterns of administration and incidence rates of all-cause and neutropenia-related hospitalization were examined on a per-cycle basis. RESULTS: In total, 9330 and 8762 patients with cancer, representing 30,264 and 24,215 chemotherapy cycles (28,189 and 22,649 (PEG), 1669 and 1351 (FIL), 406 and 215 (SAR)) from the HIRD(SM) and OptumInsight databases, respectively, were included in the separate database analyses. Both the HIRD(SM) and OptumInsight analysis showed that SAR and FIL prophylaxis had a higher risk of neutropenia-related hospitalization (SAR: OR = 3.48 [95%CI = 2.11, 5.74] and 2.81 [1.62, 4.87]; FIL: 1.78 [1.28, 2.48] and 2.36 [1.82, 3.06], respectively) and all-cause hospitalization (SAR: 2.18 [1.41, 3.36] and 2.41 [1.58, 3.68]; FIL:1.57 [1.25, 1.97] and 1.95 [1.60, 2.38], respectively) vs PEG. LIMITATIONS: Medical claims do not contain information about chemotherapy dose, and hospitalizations were not validated against the patient's chart. CONCLUSION: In this comparative effectiveness study, use of PEG was associated with a lower risk of neutropenia-related and all-cause hospitalizations compared to use of FIL or SAR prophylaxis.

Kinetics of urea and beta-microglobulin during and after short hemodialysis treatments.

BACKGROUND: Daily short hemodialysis (HD) is often prescribed by simply doubling treatment frequency and halving treatment time; however, the effect of this prescription approach on the equilibrated HD dose (urea eKt/V) and whole body clearance for beta(2)-microglobulin has not been established. METHODS: We compared urea and beta(2)-microglobulin kinetics during and 60 minutes after a short HD treatment and a conventional HD treatment in a crossover study on 22 maintenance HD patients: 16 male and 6 female, 61 +/- 18 (mean +/- standard deviation) years of age. One patient in each treatment modality was excluded from certain analyses because of missing data. Short and conventional HD treatments were essentially identical, except for treatment times, which were 116 +/- 14 and 241 +/- 27 minutes, respectively. Blood samples were collected at regular intervals during and after treatments, and additional blood and dialysate samples were collected at 60 minutes of treatment to evaluate dialyzer clearances. RESULTS: Plasma water urea clearances measured directly across the dialyzer during short and conventional HD treatments were not different (255 +/- 23 mL/min and 255 +/- 28 mL/min, respectively). The 60-minute postdialysis blood urea nitrogen concentration rebounded more (P < 0.01) after short HD than conventional HD (5.9 +/- 3.1 vs. 4.0 +/- 1.5 mg/dL, respectively). Calculated urea eKt/V values using the Daugirdas-Schneditz rate equation were not different from those measured during conventional HD using the 60-minute postdialysis concentration but significantly overestimated measured urea eKt/V values during short HD. Postdialysis rebound of beta(2)-microglobulin concentrations was variable but similar after short and conventional HD treatments (0.1 +/- 3.4 vs. 0.7 +/- 1.8 mg/L, respectively). Whole body clearances of beta(2)-microglobulin calculated from predialysis and immediate (10-second) postdialysis serum concentrations during short and conventional HD treatments were not different from each other (42.9 +/- 24.1 vs. 41.9 +/- 22.4 mL/min, respectively). CONCLUSION: These observations show that the Daugirdas-Schneditz rate equation is accurate in predicting urea eKt/V during conventional, but not during short, HD. In contrast, whole body clearances of beta(2)-microglobulin during short and conventional HD treatments were similar. We conclude that calculation of accurate estimates of urea eKt/V, but not clearances of beta(2)-microglobulin, differ during short and conventional HD treatments.

Hollow fiber shape alters solute clearances in high flux hemodialyzers.

The mass transfer properties of hemodialyzers containing hollow fiber membranes are known to be influenced by membrane chemical composition, surface area, and pore size; however, the effects of hollow fiber shape (or configuration) and packing density within the dialyzer housing have not been well characterized. We determined, both in vitro and ex vivo (clinical), solute clearances and mass transfer-area coefficients (KoA) for high flux dialyzers containing polysulfone hollow fibers of identical chemical composition but different shapes. Hemoflow F80A (1.8 m2 of membrane surface area) dialyzers contained hollow fibers with a conventional shape, but Optiflux F180A (1.8 m2), F200A (2.0 m2), and F200NR (2.0 m2) dialyzers contained hollow fibers with a wavy shape. Clearances and KoA values determined in vitro for urea and creatinine increased with increasing dialysate flow rate and were higher for Optiflux F180A and F200A dialyzers than for Hemoflow F80A dialyzers. In vitro clearances for lysozyme and myoglobin were also higher for Optiflux F180A and F200A dialyzers than for Hemoflow F80A dialyzers, suggesting that a wavy hollow fiber shape increases mass transfer by increasing effective membrane surface area, conceivably by altering dialysate flow patterns. Urea clearances and KoA values determined ex vivo were higher for Optiflux F200NR dialyzers than for Hemoflow F80A dialyzers, confirming that the in vitro results are applicable to clinical hemodialysis. These increases in mass transfer efficiency for dialyzers containing hollow fibers with a wavy shape are consistent with improved mass transfer within the dialysate compartment as evidenced by the manufacturer-reported dialysate pressure-flow relationships. We conclude that the mass transfer characteristics of high flux dialyzers can be altered by the shape of the hollow fibers.

Nonsusceptible Streptococcus pneumoniae in children with chronic otitis media with effusion and recurrent otitis media undergoing ventilating tube placement.

CONTEXT: Children with chronic otitis media are at risk for nonsusceptible Streptococcus pneumoniae (NSP) infection. If these children undergo ventilating tube placement, there is an opportunity to culture middle ear fluid and the nasopharynx to determine carriage of NSP. OBJECTIVE: To determine the incidence of NSP carriage, NSP antibiotic susceptibility and risk factors for NSP carriage in children with chronic otitis media undergoing tube placement. DESIGN AND SETTING: Prospective cohort study in an academic medical center with recruitment of patients from an otolaryngology private practice and clinic. PATIENTS: Children < 18 years of age undergoing tube placement for chronic otitis media. INTERVENTIONS: Myringotomy and tube placement, with culture of middle ear fluid and nasopharynx. MAIN OUTCOME MEASURES: The incidence of NSP cultured from the middle ears and nasopharynx of recruited subjects with the use of the minimum inhibitory concentration break points for penicillin susceptibility recommended by the National Committee for Clinical Laboratory Standards. RESULTS: S. pneumoniae was identified in at least 1 site from 23 of 300 study subjects (7.6%); of these 23, 12 case subjects (52.2%) harbored NSP. Of the risk factors assessed by preoperative questionnaire, only younger age was associated with NSP colonization (P < 0.0001). Of the six oral cephalosporins studied, cefpodoxime and cefuroxime showed good in vitro activity against S. pneumoniae isolates with intermediate penicillin resistance. CONCLUSIONS: Children with chronic otitis media undergoing tube placement may carry NSP and provide a means of monitoring the incidence of NSP and antibiotic susceptibilities for children with ear infections in their communities. Younger age is a risk factor for NSP carriage in this population.

Valacyclovir inhibits recovery of ocular HSV-1 after experimental reactivation by excimer laser keratectomy.

PURPOSE: The goal of this was to determine whether the systemic administration of valacyclovir (Valtrex) would reduce ocular shedding of herpes simplex virus 1 (HSV-1) after excimer laser ablation in the New Zealand rabbit latency model. METHODS: The in vitro 50% inhibitory concentration (IC50) of HSV-1 W strain was determined by using a plaque-reduction assay to verify its sensitivity to acyclovir. Forty-seven NZW rabbits latently infected with HSV-1 W strain were divided into four groups: I, 50 mg/kg/day valacyclovir; II, 100 mg/kg/day valacyclovir; III, 150 mg/kg/day valacyclovir; and IV, saline control. One half of the total dose of valacyclovir was delivered via intraperitoneal injections twice daily for 7 days beginning with one dose before excimer laser keratectomy. HSV-1 ocular shedding was determined from eye cultures for 7 days after treatment. RESULTS: The IC50 for HSV-1 W was determined to be 2.9 microg/ml. The administration of both 100 mg/kg/day (group II) and 150 mg/kg/day (group III) of valacyclovir significantly reduced the number of eyes from which latent HSV-1 was recovered compared with the control group. There was no difference between the control group and group I (50 mg/kg/day valacyclovir). However, all three valacyclovir dosages significantly reduced the total number of HSV-1 shedding days compared with the control group, and 100% HSV-1 TG latency was demonstrated for all four groups. CONCLUSION: Systemic administration of valacyclovir significantly reduced HSV-1 ocular shedding in a dose-dependent manner after excimer laser keratectomy in the NZW rabbit latency model.

Stability of valacyclovir hydrochloride in extemporaneously prepared oral liquids.

The stability of valacyclovir hydrochloride in three commonly used syrups was studied. Triplicate suspensions of valacyclovir (from caplets) in Ora-Sweet (Paddock Laboratories), Ora-Sweet SF (Paddock), and Syrpalta Humco Laboratory) syrups were extemporaneously compounded to yield a final concentration of valacyclovir 50 mg/mL (as the hydrochloride salt). The nine suspensions were stored at 4 degrees C in amber glass bottles. At intervals up to 60 days, the liquids were visually inspected for color change, cloudiness, gas formation, and precipitation, and samples were assayed in duplicate for valacyclovir concentration by stability-indicating high-performance liquid chromatography. Also tested were pH, particle size, and microbial growth. During the first 21 days of storage, mean valacyclovir concentrations in all liquids were >90% of the initial concentration, but concentrations were <90% by day 21 in some individual samples of suspensions prepared with Ora-Sweet and Ora-Sweet SF. Mean valacyclovir concentrations in the Syrpalta-based suspensions met the 90% cutoff for at least 35 days. Solution pH and particle size remained unchanged in all liquids through day 60, and there were no changes in physical appearance. There was no evidence of microbial growth on the days when microbial growth was tested (0 and 28). Valacyclovir 50 mg/mL (as the hydrochloride salt) in three oral liquids stored in amber glass bottles at 4 degrees C was stable for at least 21 days when prepared with two of three syrups and for at least 35 days when prepared with the third syrup. All the liquids were free of microbial growth for at least 28 days.

Rebound kinetics of beta2-microglobulin after hemodialysis.

BACKGROUND: Evaluation of beta2-microglobulin (beta2m) removal during hemodialysis using predialysis and immediate postdialysis plasma concentrations is only valid in the absence of postdialysis rebound. Postdialysis rebound of beta2m has not been studied extensively, and its importance in the determination of beta2m clearance is unknown. METHODS: We evaluated the kinetics of urea and beta2m in a crossover study of 10 chronic hemodialysis patients using dialyzers with similar urea mass transfer-area coefficients containing either low-flux cellulose acetate or high-flux cellulose triacetate membranes. Kinetics were examined during and following a 210 minute treatment by measuring plasma concentrations predialysis at regular intervals during therapy and at 0, 2, 10, 20, 30, and 60 minutes postdialysis. Clearances of urea and beta2m were also determined directly from the arterial and venous concentration differences across the dialyzer at 60 minutes after starting dialysis. RESULTS: By design, urea removal was similar for both low-flux and high-flux dialyzers as assessed by the urea reduction ratio and Kt/V. Postdialysis urea rebound was similar for low- and high-flux dialyzers; the rebound in the plasma urea nitrogen concentration (expressed as a percentage of the intradialytic decrease in plasma concentration) was 9.2 +/- 1.9% (mean +/- SEM) at 30 minutes postdialysis and 13.0 +/- 1.4% at 60 minutes postdialysis for a single pool urea Kt/V of 1.16 +/- 0.05. The plasma beta2m concentration increased by 11.1 +/- 3.0% during the treatment using the low-flux dialyzer but decreased by 27.1 +/- 4.0% during the treatment using the high-flux dialyzer. When using the high-flux dialyzer, the rebound of beta2m was 44.8 +/- 21.4% at 30 minute postdialysis and 45.9 +/- 15.9% at 60 minutes postdialysis. The clearance of beta2m for the high-flux dialyzer calculated from predialysis and immediate postdialysis plasma concentrations using a single-compartment model (28.2 +/- 4.4 ml/min) was higher (P < 0.05) than that determined directly across the dialyzer (18.3 +/- 2.0 ml/min). If either the 30- or 60-minute postdialysis plasma beta2m concentration was used instead, the calculated beta2m clearance (16. 5 +/- 4.8 ml/min or 15.6 +/- 2.8 ml/min, respectively) was similar to that determined directly across the dialyzer. CONCLUSIONS: Postdialysis rebound of beta2m when using high-flux dialyzers is substantial; neglecting postdialysis rebound results in an overestimation of beta2m clearance when calculated using a single-compartment model.

Effect of hemodialyzer reuse: dissociation between clearances of small and large solutes.

Dialyzers are reused in approximately three quarters of the dialysis units in the United States, but the effect of reprocessing on dialyzer performance has not been extensively evaluated. In a crossover study of six chronic hemodialysis patients, we determined urea, creatinine, phosphate, and beta2-microglobulin clearances and dialysate protein loss for two types of low-flux and two types of high-flux dialyzers during use numbers 1, 2, 5, and 15. Dialyzers were reprocessed by an automated machine using Renalin (Renal Systems, Plymouth, MN) as the germicide. Dialyzer arterial and venous blood and dialysate outflow samples were obtained at 5 and 180 minutes of each dialysis session to evaluate solute clearances. Urea, creatinine, and phosphate clearances were calculated using dialysate concentrations, whereas beta2-microglobulin clearance was calculated using plasma concentrations to include its removal by adsorption to the dialysis membrane. There was a trend for urea, creatinine, and phosphate clearances to decrease with reuse for both low-flux and high-flux dialyzers, but these differences were not statistically significant. The clearance of beta2-microglobulin and dialysate total protein concentration was small for low-flux dialyzers; these values were not dependent on reuse. There was a trend for beta2-microglobulin clearance and dialysate total protein concentration to decrease during a dialysis treatment using high-flux dialyzers. More significantly, beta2-microglobulin clearance and dialysate total protein concentration decreased substantially with the reuse of high-flux dialyzers. These observations show that the maintenance of small solute clearances during reuse of high-flux dialyzers does not ensure the maintenance of large solute clearances.

Single compartment models for evaluating beta 2-microglobulin clearance during hemodialysis.

Methods for evaluating dialyzer clearance of beta 2-microglobulin during clinical hemodialysis have not been well established. The authors show, theoretically, that the postdialysis-to-predialysis concentration ratio, a parameter often used to estimate dialyzer clearance of beta 2-microglobulin, depends on KdT/V (the dialyzer clearance times the treatment time divided by the distribution volume for beta 2-microglobulin) and the ultrafiltration rate, assuming that a single compartment kinetic model is valid. They also show that adjustment of the postdialysis concentration of beta 2-microglobulin for changes in its volume of distribution does not entirely correct for fluid removal when the adjusted postdialysis-to-predialysis concentration ratio is significantly below one. These considerations suggest that estimates of dialyzer clearance of beta 2-microglobulin using single compartment models are more reliable than those using only the postdialysis-to-predialysis concentration ratio. To illustrate these constructs, the authors compared experimental estimates of beta 2-microglobulin clearance during clinical hemodialysis using single compartment models with those measured directly from the arteriovenous concentration difference across the dialyzer. First-use low flux and high flux-dialyzers and those reprocessed with Renalin were studied. Single compartment estimates of beta 2-microglobulin clearance for low flux dialyzers were similar to those measured directly across the dialyzer, but single compartment estimates of beta 2-microglobulin clearance for high flux dialyzers exceeded (p < 0.001) those measured directly across the dialyzer, independent of whether fluid removal during hemodialysis was assumed to be removed entirely from the extracellular compartment or proportionally from both intracellular and extracellular compartments. The authors conclude that accurate estimates of beta 2-microglobulin clearance for high flux dialyzers will require kinetic models that are more complex than those assuming a uniform distribution of beta 2-microglobulin in a single, well-mixed compartment.

Therapy for pharyngitis and tonsillitis caused by group A beta-hemolytic streptococci: a meta-analysis comparing the efficacy and safety of cefadroxil monohydrate versus oral penicillin V.

A meta-analysis was conducted to compare the efficacy and safety of oral cefadroxil monohydrate (30 mg/kg QD or 15 mg/kg BID) with that of oral penicillin V (8, 10, or 15 mg/kg BID, TID, or QID) in the treatment of group A beta-hemolytic streptococcal (GABHS) pharyngitis and tonsillitis treated for 10 days. A simple random effects model was used for combining the efficacy and safety results of nine comparative trials performed in the United States. A total of 1646 patients aged < or = 19 years were considered evaluable; 1406 patients were evaluable using revised bacteriologic criteria, and 1499 patients were considered fully evaluable for safety. The results demonstrate significantly better response rates (P < 0.05) with cefadroxil monohydrate than with penicillin V for overall cure (91.8% versus 81.3%), bacteriologic cure (92.6% versus 81.4%), and bacteriologic recurrence (4.2% versus 10.5%); clinical cure rates were statistically similar (90.5% versus 90.2%). Revised bacteriologic criteria analysis revealed bacteriologic cure rates of 95.8% versus 88.7% (P < 0.05) and bacteriologic recurrence rates of 4.9% versus 7.1% (P = NS) for cefadroxil monohydrate and penicillin V, respectively. Adverse events related to drug administration occurred infrequently and did not differ significantly between treatment groups (P > 0.05). Compliance with cefadroxil monohydrate was at least as good as with penicillin V. Penicillin is currently the drug of choice in the treatment of GABHS pharyngitis and tonsillitis. Based on the information described in this large meta-analysis, cefadroxil monohydrate is an excellent alternative to oral penicillin V in the treatment of GABHS pharyngitis and tonsillitis.

Crossover assessment of serum bactericidal activity and pharmacokinetics of ciprofloxacin alone and in combination in healthy elderly volunteers.

To better define the pharmacokinetics and serum bactericidal activity (SBA) of ciprofloxacin and other antimicrobial agents in the elderly, six healthy (greater than 65 years) volunteers with normal renal function were given ciprofloxacin alone orally, ciprofloxacin plus rifampin orally, ciprofloxacin plus clindamycin orally, rifampin alone orally (three volunteers), and, for comparison of SBA against gram-positive cocci, vancomycin intravenously. Mean peak ciprofloxacin concentrations and other pharmacokinetic parameters were not altered significantly by coadministration of either rifampin or clindamycin. Ciprofloxacin had somewhat greater SBA against the oxacillin-susceptible and oxacillin-resistant Staphylococcus aureus strains tested than did vancomycin, but rifampin was by far the most active single agent tested. The SBA of rifampin against S. aureus was modestly antagonized during combination therapy with ciprofloxacin, but substantial SBA still was present. The ciprofloxacin SBA against S. aureus was completely antagonized by clindamycin if the strains were susceptible to the latter agent. Ciprofloxacin had modest SBA against group A streptococci and no SBA against the three pneumococcal strains tested. All of the regimens had poor to absent SBA against Enterococcus faecalis. By contrast, ciprofloxacin had excellent SBA against Escherchia coli and Klebsiella pneumoniae and moderate SBA against Pseudomonas aeruginosa. Combination therapy with rifampin or clindamycin in general enhanced the SBA against the nonenterococcal streptococci and had no effect on the SBA against the gram-negative bacilli.

Dipstick analysis of urinary protein. A comparison of Chemstrip-9 and Multistix-10SG.

The Boehringer-Mannheim Chemstrip-9 and Ames Multistix-10SG urine dipstick assays for the detection of proteinuria were evaluated. Chemstrip-9 was more precise than Multistix-10SG (13 inconsistencies vs 32 among duplicate pairs). Precision was poorest with the group of inexperienced technologists using Multistix-10SG (Chemstrip-9 yielded two inconsistencies vs 15 for Multistix-10SG) with the use of urine supplemented with protein standard. In the evaluation of both protein-supplemented and consecutively acquired patient specimens, Multistix-10SG and Chemstrip-9 performed in a statistically similar fashion regarding sensitivity and predictive value of a negative test result: supplemented sample sensitivity, patient sample sensitivity, and a predictive value of a negative test result of 90.3%, 46.8%, and 68.6%, respectively, for Multistix-10SG compared with 80.6%, 31.5%, and 63.5%, respectively, for Chemstrip-9. We conclude that neither test is sufficiently sensitive for the detection of low levels of proteinuria (1+ range) to function as a screening test for renal disease.

Respiratory tract penetration of quinolone antimicrobials: a case in study.

Antimicrobial lung penetration is thought to be predictive of efficacy in the treatment of lower respiratory tract infections. Lung penetration studies are commonly conducted with new antimicrobial agents to elucidate their potential utility in treating such infections. Although some very useful information may emerge, these studies are complicated by technical difficulties, theoretical assumptions, and numerous intricacies. Many studies describing quinolone penetration into saliva, sputum, bronchial secretions, and lung tissue have been published. In general, quinolone concentrations in lung tissue are 1.5-4 times the serum levels, whereas those in sputum and bronchial secretion are equal to or less than serum, and penetration into saliva is even less. The failure rate predicted from saliva, sputum, and bronchial secretion penetration and marginal in vitro activity of quinolones against streptococci does not consistently correlate with clinical efficacy data. In light of such conflicting data and the high lung tissue penetration of quinolones, the relevance of saliva, sputum, and bronchial secretion studies should be reevaluated. The utility of investigational quinolones in the treatment of lower respiratory tract infections can be determined only by well-designed clinical trials.

Crossover assessment of serum bactericidal activity and pharmacokinetics of five broad-spectrum cephalosporins in the elderly.

To better define the pharmacokinetics and serum bactericidal activity (SBA) of the expanded-spectrum cephalosporins in the elderly, we administered single 2-g intravenous infusions of cefoperazone, cefotaxime, ceftriaxone, ceftazidime, and ceftizoxime to six healthy volunteers over the age of 65 years. Serum was collected over 24 h, and concentrations were determined by high-performance liquid chromatography; pharmacokinetic parameters were determined for each drug. SBA was measured against representative strains of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, and Pseudomonas aeruginosa. All agents tested had excellent SBAs against E. coli and K. pneumoniae, often for a longer duration than would be expected on the basis of conventional dosing regimens. Ceftazidime had the greatest SBA against E. aerogenes and was the only agent with a substantial SBA against P. aeruginosa. Although ceftizoxime had the greatest SBA against S. aureus, none of these cephalosporins had substantial antistaphylococcal SBAs. Pharmacokinetic analysis revealed that cefoperazone and ceftriaxone had markedly different concentration-time profiles in the elderly volunteers than would have been expected on the basis of existing data from younger volunteers. For older patients, dosing guidelines for these two agents may need to be altered.

Treatment of peritonitis in patients undergoing continuous ambulatory peritoneal dialysis.

The epidemiology, etiology, pathogenesis, diagnosis, and pharmacotherapy of peritonitis in patients with end-stage renal disease treated with continuous ambulatory peritoneal dialysis (CAPD) are reviewed. CAPD-associated peritonitis is a localized infection of the peritoneal cavity. Approximately 70% of the cases are caused by a single gram-positive microorganism indigenous to the patient's skin or upper respiratory tract that infects the peritoneal cavity. Gram-negative microorganisms cause 25% of the cases; fungi, anaerobes, and mycobacteria cause approximately 5%. Clinical manifestations include a cloudy, turbid peritoneal dialysate effluent and abdominal pain or tenderness. Diagnosis is confirmed by the detection and isolation of microorganisms in the peritoneal dialysate effluent. Of patients with CAPD-associated peritonitis, 70-80% can be successfully treated on an outpatient basis with intraperitoneal (i.p.) instillation of antimicrobials. Vancomycin, cephalosporins, and aminoglycosides are the agents most commonly used to treat CAPD-associated peritonitis. Most recently, alternative dosing regimens using intermittent i.p. administration of vancomycin have been used. In certain types of CAPD-associated peritonitis (those caused by Pseudomonas aeruginosa or fungi), removal of the peritoneal catheter may be required to achieve a cure. Approximately two thirds of the patients transferring to another form of dialysis from CAPD do so because of peritonitis. Currently available data indicate that the most effective therapy for CAPD-associated peritonitis is i.p. administration of antimicrobial agents with activity against the suspected microorganism.

Therapy of otitis media.

The epidemiology, pathogenesis, diagnosis, complications and sequelae, and therapy of otitis media are reviewed. Otitis media is one of the most common infections in infants and children. Epidemiologic studies have identified season of the year, bottle versus breast feeding, socioeconomic status, race, sex, and daycare attendance as factors associated with the occurrence of otitis media. The condition is believed to arise secondary to eustachian tube dysfunction in the presence of viral or bacterial invasion of the nasopharynx. Diagnosis is often made by direct observation of the tympanic membrane with an otoscope. If untreated, the infection can spread to other structures in the aural cavity or even to the brain and meninges. The most frequent complication of otitis media is hearing loss, which may result in speech and learning difficulties. Oral antimicrobial agents--notably ampicillin, amoxicillin, amoxicillin-clavulanate, cefaclor, cefuroxime axetil, bacampicillin, cyclacillin, erythromycin ethylsuccinate-sulfisoxazole, cefixime, and trimethoprim-sulfamethoxazole--are the mainstay of treatment. Selection of the agent should be based primarily on its spectrum of activity against Streptococcus pneumoniae and Haemophilus influenzae. Other considerations include the presence of beta-lactamase-producing strains of H. influenzae and Branhamella catarrhalis, adverse effects, cost, and compliance. In cases of recurrent otitis media, antimicrobial prophylaxis or surgery may be indicated. Chronic otitis media with effusion may be treated with oral antimicrobials, but surgery may also be necessary. Chronic suppurative otitis media often requires hospitalization and intravenous antimicrobial therapy with agents effective against Pseudomonas aeruginosa. Oral antimicrobial agents represent the treatment of choice for otitis media, but such therapy addresses only one of the several etiologic factors identified.

Comparison of aminoglycoside clearance and calculated serum creatinine clearances.

Calculated creatinine clearance (CrCL) estimates are frequently used as estimates of aminoglycoside clearance (AGCL), despite being inadequately studied. Thirty surgical intensive care unit (SICU) patients with stable serum creatinines (0.6-6.3 mg/dl) and steady-state aminoglycoside levels were studied. A one-compartment pharmacokinetic infusion model was used to calculate k and Vd; AGCL = (k) (Vd). CrCLs using the equations of Cockroft-Gault (CGCL), Jelliffe (JCL), and Jelliffe uncorrected for body surface area (JCLu) were calculated, then compared to the AGCL. The JCLu was a better fit to the data (y = 0.98x + 0.44, r = 0.91) with a superior regression correlation (p less than 0.02) than CGCL (y = 0.91x + 6.07, R = 0.89) and JCL (y = 1.11x + 2.11, R = 0.89) correlations. CGCL overpredicted the AGCL whereas JCL and JCLu underpredicted the AGCL. All three methods showed a precision of approximately 20 ml/min. Relative bias and precision show JCLu better than JCL, CGCL better than JCL only for bias, and CGCL and JCLu not different. The absolute percentage error of the CrCL estimates tended to be lower at higher AGCL and did not differ for CGCL, JCL, and JCLu. In the SICU setting, we suggest the use of the JCLu for estimating the AGCL.