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.

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.

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.

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.

Pharmacokinetics of cefoperazone in ambulatory elderly volunteers compared with young adults.

Two groups of 10 healthy ambulatory subjects, i.e., a group of 10 persons less than or equal to 30 years of age (mean age, 27.6 years) and a group of 10 persons greater than or equal to 65 years of age (mean age, 70 years), were randomized in a single-trial crossover design to receive 1 and 2 g of cefoperazone with a 1-week washout between doses. The elderly subjects had both decreased estimated creatinine clearances and decreased albumin concentrations in serum. Cefoperazone concentrations in serum of elderly persons were significantly higher at each interval from 30 min to 6 h for the 2-g dose. Compared with that in younger persons, the total clearance in elderly subjects was significantly lower for both the 1- and 2-g doses, the renal clearance was significantly lower for the 2-g dose, and the area under the curve was significantly higher for the 2-g dose in the elderly persons. The half-life at beta phase was higher in the elderly persons at both the 1- and 2-g doses but not significantly so. Changes in total clearance and area under the curve and higher levels in serum in the elderly persons suggest a longer duration of antimicrobial activity in this age group.

Recent advances in antiviral therapy.

Virus replication is described, and the clinical trials and indications for amantadine, rimantadine, vidarabine, vidarabine phosphate, acyclovir, ribavirin, and other promising antiviral agents are reviewed. Amantadine and rimantadine are useful for the treatment and prophylaxis of viral influenza A infections. Vidarabine is a second-line agent and is effective for the treatment of herpes simplex encephalitis, neonatal herpes simplex types 1 and 2, and varicella-zoster infections. Vidarabine phosphate (also known as vidarabine monophosphate) has a similar spectrum of activity and can be administered in smaller volumes than vidarabine. Acyclovir has demonstrated clinical efficacy for chickenpox, shingles (herpes zoster), genital herpes, and other herpes simplex infections. Acyclovir is also useful for the suppression of herpes infections. Systemically administered ribavirin is indicated for the treatment of Lassa fever. Aerosol ribavirin is effective for the treatment of respiratory syncytial virus pneumonia in children and infants and influenza A infections in adults. Only acyclovir, amantadine, ribavirin, and vidarabine are used in clinical practice. Vidarabine phosphate and investigational agents such as rimantadine, ganciclovir (DHPG, BW B759U), phosphonoformate, and bromovinyl-deoxyuridine (BVDU) need further investigation.