Wild-type MIC distribution and epidemiological cutoff values for Aspergillus fumigatus and three triazoles as determined by the Clinical and Laboratory Standards Institute broth microdilution methods.

Antifungal susceptibility testing of Aspergillus species has been standardized by both the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Recent studies suggest the emergence of strains of Aspergillus fumigatus with acquired resistance to azoles. The mechanisms of resistance involve mutations in the cyp51A (sterol demethylase) gene, and patterns of azole cross-resistance have been linked to specific mutations. Studies using the EUCAST broth microdilution (BMD) method have defined wild-type (WT) MIC distributions, epidemiological cutoff values (ECVs), and cross-resistance among the azoles. We tested a collection of 637 clinical isolates of A. fumigatus for which itraconazole MICs were < or = 2 microg/ml against posaconazole and voriconazole using the CLSI BMD method. An ECV of < or = 1 microg/ml encompassed the WT population of A. fumigatus for itraconazole and voriconazole, whereas an ECV of < or = 0.25 microg/ml was established for posaconazole. Our results demonstrate that the WT distribution and ECVs for A. fumigatus and the mold-active triazoles were the same when determined by the CLSI or the EUCAST BMD method. A collection of 43 isolates for which itraconazole MICs fell outside of the ECV were used to assess cross-resistance. Cross-resistance between itraconazole and posaconazole was seen for 53.5% of the isolates, whereas cross-resistance between itraconazole and voriconazole was apparent in only 7% of the isolates. The establishment of the WT MIC distribution and ECVs for the azoles and A. fumigatus will be useful in resistance surveillance and is an important step toward the development of clinical breakpoints.

Photoreaction potential of orally administered levofloxacin in healthy subjects.

OBJECTIVE: To evaluate the photoreaction potential of levofloxacin on exposure to solar-simulating radiation. Solar-simulating is ultraviolet (UV) light, defined as UVA in the 320-400 nm range and UVB in the 290-320 nm range. DESIGN: In a single-center, double-blind, randomized study, 30 adults (20 men, 10 women) received oral levofloxacin (500 mg qd x 5 d) or placebo. At baseline photoexposure prior to drug administration, each subject was exposed to UVB light at 0.75, 1.0, and 2.0 times the minimal erythema dose and to UVA light (25 J/cm2). Photoexposure was repeated on day 5, two hours following final drug administration, and response was determined using both a photoreaction rating scale and investigator assessment. RESULTS: Using the photoreaction rating scale, following UVB exposure on day 5, no abnormal photoreactions were observed among levofloxacin recipients. UVA exposure was associated with mild reactions in 20 of 24 levofloxacin-treated and three of six placebo-treated subjects, with no associated symptoms. By investigator assessment, all subjects had a negative reaction to UVB photoexposure, and 10 of 24 levofloxacin-treated and three of six placebo-treated subjects had a photoreaction following UVA photoexposure. Dermal reactions were mild and similar for both treatment groups. No subject experienced an immediate wheal-and-flare reaction. There were no statistically significant differences between treatment groups for any of the comparisons. CONCLUSIONS: Levofloxacin has a low photosensitizing potential when administered to healthy subjects.

Congenital colocutaneous fistula as presenting sign of prenatally closed gastroschisis.

MATERIALS AND METHODS: An infant was born with a congenital colocutaneous fistula to the right of the base of the umbilicus, along with distal small bowel atresia. RESULTS: These findings produced a unique presentation of a prenatally closed gastroschisis with absorption of the extruded intestine. CONCLUSION: This child, like all five previously reported infants with prenatally closed gastroschisis, died from complications of short-gut syndrome.

Pharmacokinetics and safety of high-dose and extended-interval regimens of levofloxacin in human immunodeficiency virus-infected patients.

The pharmacokinetics of levofloxacin, administered in high doses and with extended dosing intervals, was studied in human immunodeficiency virus (HIV)-infected patients. Thirty patients received either 750 mg of the drug or a placebo once daily for 14 days, followed by 750 mg or 1,000 mg of the drug or a placebo three times weekly for an additional 14 days. Levofloxacin disposition was characterized by rapid oral absorption, with peak concentrations occurring approximately 1.5 h after dosing and elimination half-lives from 7.2 to 9.4 h. The overall incidence of any adverse effect was 70% (1,000 mg) to 95% (750 mg) for levofloxacin-treated patients and 71% for those taking the placebo. Levofloxacin pharmacokinetic parameters for HIV-infected patients were consistent with those observed in studies of healthy volunteers.

Separation of complex pygopagus conjoined twins.

Pygopagus twins were born with a unique spectrum of anomalies including a conjoined distal spinal cord, single kidney (in twin A), single rectum (in twin A), single vagina (in twin B), and severe central nervous system anomalies in twin B that precluded her independent survival. Separation at 10 weeks of age was tailored toward Twin A's survival. This report discusses the surgical modifications necessary in view of the unique anatomy, including salvaging the distal spinal cord and vagina for twin A.

Comparison of the effectiveness of levofloxacin and amoxicillin-clavulanate for the treatment of acute sinusitis in adults.

In this comparative trial, outpatients with acute sinusitis were randomly assigned to receive levofloxacin (500 mg orally once daily) or amoxicillin-clavulanate (500/125 mg orally 3 times daily) for 10 to 14 days. The success rates (cured and improved) 2 to 5 days after the end of treatment were 88.4% for the 267 clinically evaluable patients who received levofloxacin and 87.3% for the 268 clinically evaluable patients who received amoxicillin-clavulanate. Drug-related adverse events occurred in a smaller percentage of patients in the levofloxacin treatment group (7.4%) than in the amoxicillin-clavulanate treatment group (21.2%). The most common of these were nausea, diarrhea, vaginitis, and abdominal pain for levofloxacin-treated patients and diarrhea, vaginitis, nausea, genital moniliasis, abdominal pain, vomiting, and flatulence for amoxicillin-clavulanate-treated patients. The results of this study show that once-daily administration of levofloxacin is as effective and better tolerated than amoxicillin-clavulanate administered 3 times daily for treating acute sinusitis in adult outpatients.

Two new human neuroblastoma cell lines exhibiting tumorigenesis and metastasis in the nude mouse model.

BACKGROUND: Human neuroblastoma cell lines are notoriously difficult to establish in culture and use in murine hosts. MATERIALS AND METHODS: Two new human neuroblastoma cell lines, NK and ND, were established and studied for growth patterns in nude mice, growth in soft agar, cell cycle analysis, apoptosis (Hoechst- merocyanine 540 test), metalloproteinase expression (zymograms), and morphological differentiation by dibutyryl cyclic AMP (dCAMP). RESULTS: Both cell lines formed tumors in 6/9 nude mice within 5-31 days after subcutaneous inoculation, and metastases after intravenous tail vein injection. Both grew in soft agar. DCAMP induced morphologic differentiation in both, and inhibited cell culture growth without apoptosis. Zymograms of supernatants from cultures revealed 72-kDa metalloproteinase and higher molecular bands that did not change with dCAMP treatment. Cultures derived from murine metastatic foci exhibited 72, 82 and 85-kDa proteins, with strong 92-kDa bands after dCAMP treatment. CONCLUSION: New human neuroblastoma cell lines were established that are easily used in nude mice, and express metalloproteinases.

Levofloxacin versus ciprofloxacin versus lomefloxacin in acute pyelonephritis.

OBJECTIVES: To evaluate, in two randomized, multicenter trials, levofloxacin compared with ciprofloxacin and lomefloxacin for efficacy and safety in treating acute pyelonephritis. METHODS: We enrolled a total of 186 patients with bacteriologically proved infection. Of these, 89 patients in both trials combined received levofloxacin 250 mg once daily; 58 received ciprofloxacin 500 mg twice daily in the first trial (double blind); and 39 received lomefloxacin 400 mg once daily in the second trial (open label). Microbiologic response of patients evaluable for microbiologic efficacy was the primary efficacy variable, and clinical response of microbiologically evaluable patients was the secondary efficacy variable in both studies. RESULTS: Escherichia coli was the most prevalent pathogen. At 5 to 9 days after the end of treatment, 95% of uropathogens were eradicated in patients who received levofloxacin compared with 94% in the ciprofloxacin-treated group and 95% in the lomefloxacin-treated group. The clinical cure rate was 92% for levofloxacin in both studies combined, 88% for ciprofloxacin, and 80% for lomefloxacin. Drug-related adverse events were reported by 2% of levofloxacin-treated patients, 8% of ciprofloxacin-treated patients, and 5% of lomefloxacin-treated patients. CONCLUSIONS: The once-daily oral administration, proven efficacy, and good tolerability make levofloxacin an excellent choice for empiric treatment of acute pyelonephritis.

Levofloxacin population pharmacokinetics and creation of a demographic model for prediction of individual drug clearance in patients with serious community-acquired infection.

Population pharmacokinetic modeling is a useful approach to obtaining estimates of both population and individual pharmacokinetic parameter values. The potential for relating pharmacokinetic parameters to pharmacodynamic outcome variables, such as efficacy and toxicity, exists. A logistic regression relationship between the probability of a successful clinical and microbiological outcome and the peak concentration-to-MIC ratio (and also the area under the plasma concentration-time curve [AUC]/MIC ratio) has previously been developed for levofloxacin; however, levofloxacin assays for determination of the concentration in plasma are not readily available. We attempted to derive and validate demographic variable models to allow prediction of the peak concentration in plasma and clearance (CL) from plasma for levofloxacin. Two hundred seventy-two patients received levofloxacin intravenously for the treatment of community-acquired infection of the respiratory tract, skin or soft tissue, or urinary tract, and concentrations in plasma, guided by optimal sampling theory, were obtained. Patient data were analyzed by the Non-Parametric Expectation Maximization approach. Maximum a posteriori probability Bayesian estimation was used to generate individual parameter values, including CL. Peak concentrations were simulated from these estimates. The first 172 patients were used to produce demographic models for the prediction of CL and the peak concentration. The remaining 100 patients served as the validation group for the model. A median bias and median precision were calculated. A two-compartment model was used for the population pharmacokinetic analysis. The mean CL and the mean volume of distribution of the central compartment (V1) were 9.27 liters/h and 0.836 liter/kg, respectively. The mean values for the intercompartmental rate constants, the rate constant from the central compartment to the peripheral compartment (Kcp) and the rate constant from the peripheral compartment to the central compartment (Kpc), were 0.487 and 0.647 h(-1), respectively. The mean peak concentration and the mean AUC values normalized to a dosage of 500 mg every 24 h were 8.67 microg/ml and 72.53 microg x h/ml, respectively. The variables included in the final model for the prediction of CL were creatinine clearance (CLCR), race, and age. The median bias and median precision were 0.5 and 18.3%, respectively. Peak concentrations were predicted by using the demographic model-predicted parameters of CL, V1, Kcp and Kpc, in the simulation. The median bias and the median precision were 3.3 and 21.8%, respectively. A population model of the disposition of levofloxacin has been developed. Population demographic models for the prediction of peak concentration and CL from plasma have also been successfully developed. However, the performance of the model for the prediction of peak concentration was likely insufficient to be of adequate clinical utility. The model for the prediction of CL was relatively robust, with acceptable bias and precision, and explained a reasonable amount of the variance in the CL of levofloxacin from plasma in the population (r2 = 0.396). Estimated CLCR, age, and race were the final model covariates, with CLCR explaining most of the population variance in the CL of levofloxacin from plasma. This model can potentially optimize the benefit derived from the pharmacodynamic relationships previously developed for levofloxacin.

A controlled trial of levofloxacin and lomefloxacin in the treatment of complicated urinary tract infection.

OBJECTIVES: The efficacy and safety of levofloxacin and lomefloxacin in complicated urinary tract infections (UTIs) were compared in a randomized, open-label, multicenter study. METHODS: Outpatients were randomized to receive levofloxacin (250 mg once daily) for 7 to 10 days or lomefloxacin (400 mg once daily) for 14 days. Three hundred thirty-six patients (171 with levofloxacin, 165 with lomefloxacin) were evaluable for microbiologic efficacy, and 461 patients (232 with levofloxacin, 229 with lomefloxacin) for safety. RESULTS: The overall microbiologic eradication rate of pathogens was 95.5% (168 of 176) for levofloxacin and 91.7% (154 of 168) for lomefloxacin. Eradication rates with respect to patients were 95.3% (163 of 171) and 92.1% (152 of 165) for levofloxacin and lomefloxacin, respectively. At the 5 to 9-day post-therapy visit, symptoms were completely resolved in 84.8% of levofloxacin-treated patients and were decreased in 8.2% (93.0% clinical success). Among the lomefloxacin-treated patients, complete resolution was seen in 82.4%, with decreased symptoms in 6.1% (88.5% clinical success). Drug-related adverse events (AEs) were reported by 10 (2.6%) and 18 (5.2%) levofloxacin- and lomefloxacin-treated patients, respectively. Compared with levofloxacin-treated patients, more lomefloxacin-treated patients experienced photosensitivity reactions (3 [1.3%] versus 0) and dizziness (2 [0.9%] versus 0). Nausea (3 [1.3%] versus 1 [0.4%]) was more frequent in the levofloxacin-treated group. Six patients in each treatment group had a gastrointestinal AE (1.7%); rash was reported more frequently with lomefloxacin (4 patients [0.4%]) than with levofloxacin (1 patient [0.4%]). Discontinuation because of AEs was observed in 8 (3.4%) levofloxacin- and 14 (6.1%) lomefloxacin-treated patients. CONCLUSIONS: Once-daily levofloxacin is as effective as and has a superior tolerability profile than lomefloxacin in the treatment of complicated UTIs.

Open-label assessment of levofloxacin for the treatment of acute bacterial sinusitis in adults.

PURPOSE: To evaluate the efficacy and safety of levofloxacin (500 mg orally once daily for 10 to 14 days) in treating adult outpatients with acute bacterial sinusitis. PATIENTS AND METHODS: A total of 329 patients enrolled in the study at 24 centers. All patients had a pre-therapy Gram's stain and culture of sinus exudate obtained by antral puncture or nasal endoscopy. Clinical response was assessed on the basis of signs and symptoms and sinus radiograph or computed tomography results. Microbiologic cure rates were determined on the basis of presumed plus documented eradication of the pre-therapy pathogen(s). RESULTS: The most common pathogens were Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, and Moraxella catarrhalis. Of 300 clinically evaluable patients, 175 (58%) were cured and 90 (30%) were improved at the post-therapy evaluation, resulting in a clinical success rate of 88%. Thirty-five patients (12%) clinically failed treatment. The microbiologic eradication rate (presumed plus documented) among 138 microbiologically evaluable patients was 92%. Microbiologic eradication rates (presumed plus documented) of the most common pathogens ranged from 93% (M. catarrhalis) to 100% (S. pneumoniae) at the post-therapy visit. All but one of the 265 patients who were cured or improved at post-therapy returned for a long-term follow-up visit; 243 (92%) remained well 4 to 6 weeks after therapy; and 21 (8%) had a relapse of symptoms. Adverse events considered to be related to levofloxacin administration were reported by 29 patients (9%). The most common drug-related adverse events were diarrhea, flatulence, and nausea; most adverse events were mild to moderate in severity. CONCLUSION: The results of this study indicate that levofloxacin 500 mg once daily is an effective and safe treatment for acute bacterial sinusitis.

Intraabdominal leg: unique variant of split notochord syndrome.

An infant was born with a spectrum of anomalies representing a unique variant of the split notochord syndrome. The major anomalies included giant omphalocele and duplicated lower spine, between which developed a posterior lumbosacral mass that was contiguous with an intraabdominal, skin-covered "leg" within a saccular cecum. Features of this case overlap aspects of fetiform teratoma, fetus-in-fetu, conjoined twins, and caudal duplication, suggesting an etiologic relation between these entities and split notochord syndrome.

Double-blind evaluation of the safety and pharmacokinetics of multiple oral once-daily 750-milligram and 1-gram doses of levofloxacin in healthy volunteers.

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (Cmax) values were generally attained within 2 h postdose. The mean values of Cmax and area under the concentration-time curve from 0 to 24 h (AUC0-24) following a single 750-mg dose were 7.1 microg/ml and 71.3 microg x h/ml, respectively, compared to 8.6 microg/ml and 90.7 microg x h/ml, respectively, at steady state. Following the single 1-g dose, mean Cmax and AUC0-24 values were 8.9 microg/ml and 95.4 microg x h/ml, respectively; corresponding values at steady state were 11.8 microg/ml and 118 microg x h/ml. These Cmax and AUC0-24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (Vss/F), half-life (t1/2), and renal clearance (CL[R]) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, Vss/F, t1/2, and CL(R) following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.

Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials.

CONTEXT: One purpose of early clinical trials is to establish the appropriate dose of an antibiotic for phase 3 trials. Development of a relationship between the ratio of drug exposure to organism minimum inhibitory concentration (MIC) and therapeutic response early in the development process would allow an optimal choice of dose to maximize response. OBJECTIVE: To prospectively quantitate the relationship between plasma levels of levofloxacin and successful clinical and/or microbiological outcomes and occurrence of adverse events in infected patients. DESIGN: Multicenter open-label trial. SETTING: Twenty-two enrolling university-affiliated medical centers. PATIENTS: A total of 313 patients with clinical signs and symptoms of bacterial infections of the respiratory tract, skin, or urinary tract. MAIN OUTCOME MEASURES: Clinical response and microbiological eradication of pathogenic organisms. RESULTS: Of 313 patients, 272 had plasma concentration-time data obtained. Of these, 134 patients had a pathogen recovered from the primary infection site and had an MIC of the pathogen to levofloxacin determined. These patients constituted the primary analysis group for clinical outcome. Groups of 116 and 272 patients, respectively, were analyzed for microbiological outcome and incidence of adverse events. In a logistic regression analysis, the clinical outcome was predicted by the ratio of peak plasma concentration to MIC (Peak/MIC) and site of infection (P<.001). Microbiological eradication was predicted by the Peak/MIC ratio (P<.001). Both clinical and microbiological outcomes were most likely to be favorable if the Peak/MIC ratio was at least 12.2. CONCLUSIONS: Levofloxacin generated clinical and microbiological response rates of 95% and 96%, respectively. These response rates included fluoroquinolone "problem pathogens," such as Streptococcus pneumoniae and Staphylococcus aureus. Exposure to levofloxacin was significantly associated with successful clinical and microbiological outcomes. The principles used in these analyses can be applied to other classes of drugs to develop similar relationships between exposure and outcome. This pharmacokinetic modeling could be used to determine optimal treatment dose in clinical trials in a shorter time frame with fewer patients. This modeling also should be evaluated for its potential to improve outcomes (maximizing therapeutic response, preventing emergence of resistance, and minimizing adverse events) of patients treated with this drug.

Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses.

The pharmacokinetics of once-daily oral levofloxacin (study A) or intravenous levofloxacin (study B) in 40 healthy male volunteers were investigated in two separate randomized, double-blind, parallel-design, placebo-controlled studies. Levofloxacin at 500 mg or placebo was administered orally or intravenously as a single dose on day 1; daily oral or intravenous dosing resumed on days 4 to 10. In a third study (study C), the comparability of the bioavailabilities of two oral and one intravenous levofloxacin formulations were investigated with 24 healthy male subjects in an open-label, randomized, three-way crossover study. Levofloxacin at 500 mg as a single tablet or an intravenous infusion was administered on day 1; following a 1-week washout period, subjects received the second regimen (i.e., the other oral formulation or the intravenous infusion); the third and final regimen was administered following a 1-week washout period. The concentrations of drug in plasma and urine were measured by validated high-pressure liquid chromatography methods. Pharmacokinetic parameters were estimated by noncompartmental methods. In both study A (oral levofloxacin) and study B (intravenous levofloxacin), steady state was attained within 48 h after the start of the multiple dosing on day 4. Levofloxacin pharmacokinetics were linear and predictable for the single and multiple 500-mg, once-daily oral and intravenous dosing regimens, and the values of the pharmacokinetic parameters for the oral and intravenous administrations were similar. Study C indicated that levofloxacin was rapidly and completely absorbed from the oral tablets, with mean times to the maximum concentration of drug in serum of approximately 1.5 h and mean absolute bioavailability of > or =99%. These results support the interchangeability of the oral and intravenous routes of levofloxacin administration.

Absence of a pharmacokinetic interaction between intravenous theophylline and orally administered levofloxacin.

A randomized, placebo-controlled, two-way crossover study in 16 healthy men was performed to determine the effect of orally administered levofloxacin at steady-state conditions, given at 500 mg every 12 hours, on the pharmacokinetics of theophylline given as a single 4.5-mg/kg intravenous infusion. Participants were assigned randomly to receive theophylline with levofloxacin in one study period and theophylline with placebo in the other period. Fourteen individuals completed the study. Mean (+/-SD) values for theophylline pharmacokinetic parameters for the levofloxacin and placebo treatments, respectively, were peak plasma concentrations (Cmax) of 11.4 (1.8) micrograms/mL and 10.7 (1.3) micrograms/mL; areas under the concentration time curve from time 0 extrapolated to infinity (AUCzero-infinity) of 124 (32) micrograms.hr/mL and 126 (30) micrograms.hr/mL; volumes of distribution at steady state (Vdss) 31.7 (3.5) L and 32.0 (3.9) L; clearances (Cl) of 48.6 (11.6) mL/min and 47.4 (10.3) mL/min; and half-lives (t1/2) of 8.1 (1.9) hours and 8.2 (1.8) hours. There were no statistically significant differences between treatments for any of these parameters. There was no pharmacokinetic interaction between levofloxacin administered orally at steady-state conditions and intravenously administered theophylline.

New application of endoloop for rectal polypectomy.

The primary difficulty in performing rectal procedures such as polypectomy in children is the limited space in which to suture after a biopsy. Use of an available laparoscopic pretied loop ligature has been adapted to simplify these cases.

Subclavian artery compression from a chest tube after thoracotomy in a premature infant.

A premature baby underwent thoracotomy for repair of esophageal atresia and tracheoesophageal fistula, during which time a right chest tube was placed. In the immediate postoperative period, right subclavian artery occlusion was recognized and relieved by partial withdrawal of the chest tube, which had migrated high into the apex of the right hemithorax.

Percutaneous dilational tracheostomy in children and teenagers.

Percutaneous dilational tracheostomy (PDT) is a new technique that has been successfully performed in adult patients who required long-term mechanical ventilation, but it has not been used in children. The authors report their initial experience with PDT in 11 children and teenagers. The procedure is as follows. Using Seldinger's technique, the trachea is cannulated with a guide-wire. It is then progressively dilated, to an appropriately sized tract, with dilators from a commercially available kit. Then, a tracheostomy tube can be inserted into the trachea, loaded over a dilator. Eleven children, aged 10 to 20 years, underwent PDT in an average of 20 minutes. In eight cases, PDT was performed at the bedside. One intraoperative and one postoperative complication developed in the same patient; both complications were easily recognized and treated. Tracheal stenosis has not developed in eight decannulated patients at an average of 43 +/- 30 weeks after decannulation. PDT appears to be a safe, potentially cost-effective alternative to open tracheostomy in young patients.